P38 kinase inhibitors reduce dux4 and downstream gene expression for the treatment of fshd

ABSTRACT

The disclosure relates to methods and compositions including p38 kinase inhibitors and agents that regulate expression of DUX4 and downstream genes including but not restricted to ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2, KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6, PRAMEF15, or ZNF280A. Methods useful for treating a disease associated with abnormal DUX4 and downstream gene expression (e.g., Facioscapulohumeral muscular dystrophy) are disclosed.

RELATED APPLICATIONS

This application is a continuation application of InternationalApplication No. PCT/US2018/054642, filed on Oct. 5, 2018, which claimspriority to U.S. Provisional Application No. 62/568,673, filed on Oct.5, 2017; U.S. Provisional Application No. 62/568,754, filed on Oct. 5,2017; U.S. Provisional Application No. 62/682,563, filed on Jun. 8,2018; and U.S. Provisional Application No. 62/682,565, filed on Jun. 8,2018; all of which are incorporated by reference herein in theirentireties.

INCORPORATION OF SEQUENCE LISTING

The contents of the text file named “FULC-02602US_SeqList,” which wascreated on Oct. 17, 2018, and is 3 KB in size, are hereby incorporatedby reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to methods of inhibiting p38 kinase forreduction of DUX4 expression levels and/or downstream gene and proteinexpression and the treatment of diseases associated with DUX4.

BACKGROUND OF THE INVENTION

The muscular dystrophies (MD) are a group of more than 30 differentgenetic diseases characterized by progressive weakness and degenerationof the skeletal muscles that control movement. Some forms of MD occur ininfancy or childhood, while others may not appear until middle age orolder. The various MD diseases differ in terms of the distribution andextent of muscle weakness (some forms of MD also affect cardiac muscle),age of onset, rate of progression, and pattern of inheritance.

Facioscapulohumeral muscular dystrophy (FSHD) is the third most commonform of muscular dystrophy and affects approximately 1 in 15,000 peopleworldwide. FSHD is caused by genetic mutations resulting in theepigenetic derepression of the DUX4 gene, which makes this diseaseunique among muscular dystrophies. FSHD's primary manifestations areweakness and wasting of muscles of the face, shoulder girdle, upperarms, and trunk, and impacts lower extremities in more severe cases.

Genetic mutations associated with FSHD lead to a partial decompaction ofthe D4Z4 chromatin structure and a resulting failure to repress DUX4, atranscription factor encoded by the D4Z4 unit, in skeletal muscle.FSHD1, representing about 95% of FSHD cases reported, is associated withdeletions of macrosatellite D4Z4 repeats in the subtelomeric region ofchromosome 4q35, leaving 1-10 D4Z4 repeats (reviewed in Tawil et. al.,2014). FSHD2 is caused by mutations in Structural Maintenance ofChromosomes Flexible Hinge Domain Containing 1 gene (SMCHD1) onchromosome 18 (reviewed in van der Maarel et. al., 2007). Both FSHD1 andFSHD2 mutations lead to loss of repression at the 4q35 D4Z4 repeatarray, allowing aberrant transcription in muscle of a full-length formof Double homeobox 4, DUX4, mRNA (DUX4 fl, which encodes the doublehomeobox 4 (DUX4) transcription factor (Tawil et. al., 2014). DUX4 flRNA isoforms found associated with FSHD vary only in the 3′ untranslatedregion and have no identified functional distinction.

There is currently no approved treatment that can halt or reverse theeffects of FSHD, although nonsteroidal anti-inflammatory drug are oftenprescribed to improve comfort and mobility. Clearly, therefore, there isa need in the art for new methods for reducing the expression levels ofDUX4, e.g., DUX4-fl mRNA and/or DUX4 protein, e.g., to treat FSHD andother diseases. The present invention meets this need.

SUMMARY OF THE INVENTION

In one aspect, a method for treating a disorder responsive to p38 kinaseinhibition is provided. The method includes administering to a subjectin need thereof, an effective amount of a p38 kinase inhibitor ofFormula V′:

or a stereoisomer thereof, an isotopically-enriched compound thereof, aprodrug thereof, a solvate thereof, or a pharmaceutically acceptablesalt thereof. The method includes the treatment of disorders associatedwith DUX4 gene expression, wherein the inhibition of p38 kinase with ap38 kinase inhibitor may reduce DUX4 expression levels and/or theexpression of one or more downstream genes in cells of the subject.

In another aspect, a method for treating facioscapulohumeral musculardystrophy (FSHD) is provided. The method includes administering to asubject in need thereof, an effective amount of a p38 kinase inhibitorof Formula V′, or a stereoisomer thereof, an isotopically-enrichedcompound thereof, a prodrug thereof, a solvate thereof, or apharmaceutically acceptable salt thereof.

In one aspect, a method for treating a disorder responsive to p38 kinaseinhibition is provided. The method includes administering to a subjectin need thereof, an effective amount of a p38 kinase inhibitor selectedfrom one or more of the following Formulae I′-XXIX′:

or a stereoisomer thereof, an isotopically-enriched compound thereof, aprodrug thereof, a solvate thereof, or a pharmaceutically acceptablesalt thereof. The method includes the treatment of disorders associatedwith DUX4 gene expression, wherein the inhibition of p38 kinase with ap38 kinase inhibitor may reduce DUX4 expression levels and/or theexpression of one or more downstream genes in cells of the subject.

In another aspect, a method for treating facioscapulohumeral musculardystrophy (FSHD) is provided. The method includes administering to asubject in need thereof, an effective amount of a p38 kinase inhibitorselected from one or more of Formulae I′-XXIX′, or a stereoisomerthereof, an isotopically-enriched compound thereof, a prodrug thereof, asolvate thereof, or a pharmaceutically acceptable salt thereof.

In one aspect, a method for treating a disorder responsive to p38 kinaseinhibition is provided. The method includes administering to a subjectin need thereof, an effective amount of a p38 kinase inhibitor selectedfrom one or more of Formulae I-XIII (of Genuses I-XIII describedherein), or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof. The method includes the treatment of disordersassociated with DUX4 gene expression, wherein the inhibition of p38kinase with a p38 kinase inhibitor may reduce DUX4 expression levelsand/or the expression of one or more downstream genes in cells of thesubject.

In another aspect, a method for treating facioscapulohumeral musculardystrophy (FSHD) is provided. The method includes administering to asubject in need thereof, an effective amount of a p38 kinase inhibitorselected from one or more of Formulae I-XIII (of Genuses I-XIIIdescribed herein), or a stereoisomer thereof, an isotopically-enrichedcompound thereof, a prodrug thereof, a solvate thereof, or apharmaceutically acceptable salt thereof.

In one aspect, a method for treating a disorder responsive to p38 kinaseinhibition is provided. The method includes administering to a subjectin need thereof, an effective amount of a p38 kinase inhibitor, or astereoisomer thereof, an isotopically-enriched compound thereof, aprodrug thereof, a solvate thereof, or a pharmaceutically acceptablesalt thereof. The method includes the treatment of disorders associatedwith DUX4 gene expression, wherein the inhibition of p38 kinase with ap38 kinase inhibitor may reduce DUX4 expression levels and/or theexpression of one or more downstream genes in cells of the subject.

In several embodiments, a method for treating facioscapulohumeralmuscular dystrophy (FSHD) is provided. The method includes administeringto a subject in need thereof, an effective amount of a p38 kinaseinhibitor described herein, or a stereoisomer thereof, anisotopically-enriched compound thereof, a prodrug thereof, a solvatethereof, or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B show expression of DUX4 protein and RNA in FSHDmyotubes. FIG. 1A includes micrographs of FSHD myotubes stained using anantibody that binds DUX4 protein and/or DAPI (to detect nuclei). MatureFSHD myotubes showed actin striations in culture (not shown) andexpressed DUX4 protein in discrete sets of nuclei contained within adifferentiated myotube (FIG. 1A). FIG. 1B is a graph showing relativeexpression of DUX4 mRNA in FSHD myotubes and myotubes from an isogenicwild type (healthy) control.

FIG. 2 is a graph showing mRNA expression of the indicated DUX4regulated genes in wild type myotubes treated with DMSO, or FSHDmyotubes treated with FTX-2 or DMSO. For each indicated gene, the barsfrom left to right correlate to wild type myotubes treated with DMSO,FSHD myotubes treated with DMSO, and FSHD myotubes treated with FTX-2(DUX4-targeted ASO).

FIGS. 3A-3C show reduction of MBD3L2 mRNA in FSHD myotubes treated withDUX4-targeted ASOs. MBD3L2 was normalized to POLR2A mRNA as measured byqPCR. FIG. 3A is a graph showing grouped plate quality control datacomparing MBD3L2 expression in FSHD myotubes treated with DMSO controlor 1 μM DUX4-targeted ASOs, and healthy normal isogenic wild-typemyotubes (WT). FIG. 3B is a graph showing dose-dependent reduction ofMBD3L2 mRNA expression in FSHD myotubes treated with different dilutionsof the DUX4-targeted ASO (FTX-2). FIG. 3C shows plate-based assaystatistics comparing MBD3L2 signal in FSHD myotubes treated with DMSO toDUX4-targeted ASOs or wild type myotubes treated with DMSO.

FIGS. 4A-4D are graphs showing expression levels of MBD3L2 mRNA and MYOGmRNA in FSHD myotubes treated with the indicated p38α/β inhibitorsrelative to treatment with DMSO control. The p38α/β inhibitors includedSB 239063 (FIG. 4A), VX-702 (FIG. 4B), Pamapimod (FIG. 4C), and TAK-715(FIG. 4D). The structures of the inhibitors are also provided.

FIGS. 5A and 5B show data from FSHD myotubes treated with Pamapimod.FIG. 5A is a graph showing that dose-dependent reduction in DUX4-fl mRNA(filled circles) and MBD3L2 mRNA (open circles). FIG. 5B showsmicrographs of FSHD myotubes treated with either DMSO or Pamapimod.

FIGS. 6A-6C are graphs showing mRNA levels of MAPK14 (FIG. 6A) andMBD3L2 (FIG. 6B and FIG. 6C) in FSHD myotubes treated with siRNAstargeting p38a MAPK14 (siMAPK14 85 and siMAPK14 86; FIG. 6A and FIG. 6B)or treated with p38a kinase (MAPK14 and DUX4 pLAM) Cas9/sgRNA RNPs (FIG.6C), as compared to non-targeting control (NT CTRL). In FIG. 6C, foreach treatment, the results shown left to right correspond to MBD3L2 andMYOG, respectively.

FIG. 7 is a graph showing expression levels of DUX4 protein, MBD3L2mRNA, and p-HSP27 protein in FSHD myotubes following treatment withincreasing dosages of FTX-1821 (structure shown), as a percentage ofDMSO control treatment levels. Bars represent standard deviation.

FIGS. 8A and 8B show the effect of FTX-1821 on myotube formation. FIG.8A provides representative images of morphology of immortalized FSHDmyotubes obtained after treatment with vehicle (DMSO) or the indicatedconcentrations of FTX-1821, and staining with antibodies against MHC andDAPI (nuclear stain). FIG. 8B is a graph showing quantification ofnuclei in myotubes, as defined by MEW staining, after treatment withFTX-1821 at concentrations tested. Bars represent standard deviation ofthree replicates.

FIGS. 9A and 9B show the results of apoptosis assays in FSHD myotubes invitro. FIG. 9A provides micrographs of FSHD myotubes stained for activecaspase-3 (as a marker of apoptosis) or DAPI. Apoptosis was detected ina sporadic manner in a subset of myotubes in culture as shown by whitecircles in the left panel and in the magnified region to the right. FIG.9B is a graph showing quantification of active caspase-3 signal in FSHDmyotubes treated with the indicated concentrations of FTX 1821.

FIGS. 10A and 10B illustrate the identification of genes downregulatedin FSHD myotubes by FTX-1821. FIG. 10A is a heatmap, which illustratesdifferentially expressed genes identified by RNA-seq profiling. Threereplicates for each condition were analyzed by RNA-seq and genes wereclustered by the direction and intensity of change as indicated. Thecolor bar indicates the normalized changes observed, e.g., genes thatwere downregulated by FTX-1821 are enriched in samples treated with onlyDMSO. Down-regulated genes are listed in FIG. 10A. FIG. 10B is a graphshowing the normalized expression level reads of the DUX4 target genesthat were downregulated upon treatment with FTX-1821 in wild type cellstreated with vehicle control DMSO, FSHD cells treated with DMSO, or FSHDcells treated with FTX-1821.

FIG. 11 is a graph showing mRNA expression levels by qRT-PCR of the DUX4target gene, MBD3L2 (normalized to POLR2A), in myotubes derived fromfour distinct FSHD patient myoblast lines, FTCE-016, -020, -197, -196and two wild type (WT) control lines, following the indicated treatmentwith DMSO vehicle control, FTX-1821 or FTX-839.

FIGS. 12A and 12B provide information on various p38 kinase inhibitors.FIG. 12A is a table of data summarizing pharmacology for the indicatedp38α and β inhibitors, including IC₅₀ for reducing MBD3L2 expression inFSHD cells. Comparable MBD3L2 IC₅₀ values are shown, indicatinginhibition of DUX4 downstream gene expression in FSHD myotubes across abroad structural panel of p38α and β inhibitors reported to have similarenzyme potencies. These data indicate that p38 inhibition result in DUX4target gene, MBD3L2, reduction IC₅₀ values in the range of ˜6-68 nM.FIG. 12B provides the compound structures of the p38 kinase inhibitorslisted in FIG. 12A.

FIG. 13 is a table of various cell lines utilized in “clinical trial ina dish,” which shows diversity of genotypes, and includes both primaryand immortalized lines, as well as FSHD1 and FSHD2 patient lines.

FIGS. 14A and 14B are graphs showing MBD3L2 mRNA expression normalizedto POLR2A (by qRT-PCR) (FIG. 14A) and apoptosis as measured by cleavedcaspase-3 (FIG. 14B) determined in nine FSHD1 and three FSHD2 patientmyotubes (listed in Table 2, FIG. 14B contains only 2 FSHD2 cell lines)following treatment with FTX-1821, FTX-839, or DMSO vehicle control.

FIG. 15. is a graph showing the time course of plasma exposure,trapezius muscle exposure and p38 target engagement(Phosphorylated-p38α: Total p38α Ratio) in the rat following oraladministration of 0.3 mg/kg FTX-1821.

FIG. 16. is a graph showing MBD3L2 mRNA levels in A4 and C6 xenograftedTA muscles.

FIG. 17. is a graph showing phosphor/total MC2 ratio in mouse trapeziusmuscles following treatment with vehicle control or p38 kinaseinhibitor, FTX-2865.

FIG. 18. is a graph showing MBD3L2 mRNA levels in C6 xenografted TAmuscles following treatment with vehicle control or p38 inhibitor,FTX-2865.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based, in part, on the discovery thatinhibition of p38 kinase, e.g., p38-α, results in reduced expression ofDUX4 and downstream genes regulated by DUX4. Accordingly, the inventionincludes methods and compositions related to using an inhibitor of p38,e.g., p38-α, (alone or in combination with another agent) to reduce theexpression and/or activity levels of DUX4 and/or any of its downstreamtarget genes, e.g., in the treatment or prevention of diseasesassociated with aberrant DUX4 expression, such as FSHD, a type ofmuscular dystrophy.

The muscular dystrophies are a diverse group of genetic diseases thatcause progressive weakness of the body's muscles. Some types of musculardystrophy will present symptoms in early childhood, while other typeswill appear in adulthood. Different muscle groups also may be affecteddepending on the type of muscular dystrophy. See, e.g., Isin Dalkilicand Louis M Kunkel. Nearly 30 genes are known to give rise to variousforms of muscular dystrophy, which differ in age of onset, severity, andmuscle groups affected. The number of genes identified increases eachyear, adding to our understanding as well as revealing the overallcomplexity of the pathogenesis of these diseases.

For example, two common muscular dystrophies Duchenne Muscular Dystrophy(DMD) and Facioscapulohumeral dystrophy (FSHD) are considered to beunique diseases with some shared characteristics. Similarities betweenDMD and FSHD include that both are genetic diseases and symptoms includemuscle loss with muscle weakness leading to disability (therefore bothDMD and FSHD are grouped in the large category of muscular dystrophies,which means muscle degeneration). However, DMD and FSHD have verydifferent etiology and disease diagnosis (dystrophin loss in DMD vsexpression of DUX4-myotoxin in FSHD). For example, in DMD, mutations inthe DMD gene (>2000 known) result in dysfunctional or missingdystrophin. In FSHD, the disease is due to overexpression of the DUX4gene in muscle tissue; it is not due to point mutations in the gene(DUX4 protein is expressed when the number of D4Z4 repeats in the DUX4gene is between 1 and 8, or when repression is lost at the D4Z4 bymutations in other silencing machinery). Other differences include thatonly skeletal muscle is involved in FSHD, whereas both skeletal andcardiac muscle are affected in DMD; the diaphragm is involved in DMD butnot FSHD; generally there is childhood onset in DMD but adult/adolescentonset in FSHD; and onset with ambulatory involvement in DMD but onsetwith face and proximal arm/shoulders in FSHD. Another importantdistinction is that there is response to steroids in DMD but not inFSHD. In addition, the approved treatment for DMD (Exondys-51 in the US;Ataluren in the EU) will not have any effect in FSHD. Finally, onlymales are affected in DMD while there is equal involvement of both sexesin FSHD.

FSHD also has an unusual pathology, and it is unique among musculardystrophies in that its development requires both genetic and epigeneticconditions. The genetic condition is the presence of a complete DUX4gene. The DUX4 gene is a retrogene normally expressed in germ line andearly embryonic cells, but it is repressed by D4Z4 repeat-inducedsilencing in adult tissues (Ehrlich and Lacey, 2012). Each D4Z4 elementcontains a promoter and the DUX4 ORF, but lacks a polyadenylation signal(PAS), resulting in rapid DUX4 mRNA degradation. In contrast,transcripts initiated in the distal D4Z4 unit on a 4qA permissive alleleextend outside of the repeat array and reach a PAS in the flanking pLAMsequence (reviewed in Tawil et al., 2014; Himeda et al., 2015). Theresulting poly-A tail stabilizes the DUX4 mRNAs and allows for theirtranslation into a protein that is not normally expressed in healthymuscle and is toxic to skeletal muscle function. Two enhancers, DUX4myogenic enhancer 1 (DME1) and DME2, which activate DUX4-fl expressionin skeletal myocytes, have been described to regulate DUX4-fl expressionin FSHD (Himeda et al., 2014).

FSHD1, FSHD2 and stages in early development as well as germlineformation stages appear to confer a transcriptionally permissiveconformation to D4Z4 chromatin. This is evidenced by changes in histonemodification, partial but variable hypomethylation of D4Z4 in FSHD1, andmore extensive hypomethylation in FSHD2 (Himeda et al., 2015). However,D4Z4 hypomethylation does not suffice for the disease, since there is anabsence of muscular dystrophy symptoms in patients with ICF(immunodeficiency, centromeric region instability and facial anomalies),a rare, unrelated DNA hypomethylation-associated disease in which D4Z4is strongly hypomethylated (OMIM Entry—#614069).

DUX4 is a homeobox transcription factor protein, and expression of DUX4in muscle induces a transcriptional program leading to expression ofdownstream genes and protein products that are not normally expressed inskeletal muscle. For example, DUX4 expression results in the inductionof several germline genes in FSHD skeletal muscles and in transfectedcells (Yao et al, 2014; Ehrlich and Lacey, 2012). Many of these noveltranscripts are expressed in FSHD muscle cells but not in control musclecells (Yao et al., 2014; Homma et al., 2015; Shadle et al., 2017;Bosnakovski et al., 2014). Since some of the downstream target genes ofDUX4 encode transcription factors, DUX4 pathological activation leads toa large gene expression deregulation cascade in muscle, which causes thedisease (Yao et al., 2014; Homma et al., 2015; Shadle et al., 2017;Bosnakovski et al., 2014).

Endogenous (in the FSHD myofiber) and forced DUX4 expression in musclecells is toxic, leads to apoptosis and oxidative stress, and interfereswith myogenesis and sarcomere function (Rickard et al., 2015; Homma etal., 2015; Bosnokovski et al., 2014; Tawil et al., 2014; Himeda et al.,2015). Clinical heterogeneity in both disease progression and age ofonset can be accounted for, in part, by epigenetic instability leadingto progressive changes in DUX4 transcription. The role of DNAhypomethylation and permissive DUX4 transcription is exemplified by thehigh clinical severity observed in patients who inherited combined FSHD1and 2 defects (reviewed in Tawil et al., 2014; van der Maarel et al.,2007). Clinical heterogeneity is also explained by differences in theseverity of D4Z4 repeat shortening, with more severe phenotype andyounger age at onset in patients with shorter repeats (1-3) compared topatients with less severely contracted repeats (4-7).

DUX4 is now recognized as the cause of the pathology of FSHD, sinceactivation of its target genes is the main molecular signature in FSHDmuscle (Reviewed in Tawil et al., 2014; Himeda et al., 2015). Majordownstream target genes are members of highly homologous gene familiesthat are clustered spatially on chromosomes, including PRAMEF(preferentially expressed in melanoma), TRIM (tripartitemotif-containing), MBDL (methyl-CpG binding protein-like), ZSCAN (zincfinger and SCAN domain containing) and RFPL (ret-finger protein-like)families (Geng et al., 2012; Yao et al., 2014; Shadle et al., 2017;Ehrlich and Lacey, 2012; Tawil et al., 2014; van der Maarel et al.,2007). Discrimination between FSHD and control skeletal muscle can bemade using ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2, KHDC1L, RFPL2, CCNA1,SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6, PRAMEF15, ZNF280Aetc. (described in but not limited to Yao et al., 2014; Shadle et al.,2017; Ehrlich and Lacey, 2012).

Annotated chemical probes were screened to identify disease-modifyingsmall molecule drug targets that reduce DUX4 expression in FSHDmyotubes. These screens identified multiple chemical scaffolds thatinhibit p38 mitogen-activated protein kinase alpha (MAPK14 or p38-α). Asdescribed in the accompanying Examples, it has been shown that knockdownof the MAPK14 gene using small interfering RNA (siRNA) technology orCRISPR-mediated genome editing with specific guide RNA's (gRNAs) thatselectively target the alpha isoform of p38 kinase also reduces DUX4 andDUX4-related downstream gene expression in FSHD myotubes. It was alsofound that selective p38α and β kinase inhibitors specifically reducedDUX4 and its downstream genes in FSHD myotubes, thereby impacting thecore pathophysiology of the FSHD disease process (data exemplifiedherein). The same experiments revealed that p38α and β kinase inhibitorsdo not impact myogenin or the expression of other myogenic factors, nordo they impact proliferation of myoblasts or differentiation ofmyoblasts exhibited by myogenic fusion in FSHD myotubes. These p38kinase inhibitor small molecules reduce the expression of DUX4 andrelated downstream genes, thereby impacting pathophysiology of the FSHDdisease process, including reducing apoptotic cell death. p38-mediatedDUX4 reduction would be expected to impact downstream inflammatory,fatty infiltration and fibrotic processes in FSHD.

Members of the p38 MAPK family, composed of α, β, γ and δ, isoforms areencoded by separate genes that play a critical role in cellularresponses needed for adaptation to stress and survival (reviewed inWhitmarsh 2010; Martin et al., 2014; Krementsov et al., 2013). In manyinflammatory diseases, including cardiovascular and other chronicdiseases, these same p38 MAPK stress-induced signals can triggermaladaptive responses that aggravate, rather than alleviate, the disease(reviewed in Whitmarsh 2010; Martin et al., 2014). Indeed, in skeletalmuscle, a variety of cellular stresses including chronic exercise,insulin exposure and altered endocrine states, myoblast differentiationinto myocytes, reactive oxygen species, as well as apoptosis, have allbeen shown to induce the p38 kinase pathway (Keren, et. al., 2006;Zarubin et al., 2006). In fact, the p38 kinase pathway can be activatedby a number of external stimuli, including pro-inflammatory cytokinesand cellular stress, leading to activation of the dual-specificity MAPKkinases MKK3 and MKK6. Activation of MKK3 and MKK6, which in turnphosphorylate p38 in its activation loop, trigger downstreamphosphorylation events. These include phosphorylation of HSP27, MAPKAPK2(MK2) and a variety of transcription factors culminating intranscriptional changes in the nucleus. A modest number of p38-regulatedtranscripts and a large number of downstream effectors of p38 kinasehave been identified (described in Cuenda et al., 2007 and Kyriakis et.al., 2001, Viemann et al. 2004).

Several compounds from different chemical scaffolds that inhibit thep38α MAPK signaling pathway have entered clinical trials in diverse(non-neuromuscular) indications, including rheumatoid arthritis, chronicobstructive pulmonary disease, pain, cardiovascular diseases, andcancer. Inhibition of p38α and β in clinical trials has proven to besafe but not efficacious in any of these indications. In vitro and invivo pharmacology suggest that p38α target engagement in these clinicalstudies was robust, as demonstrated by measuring reduction inphosphorylation of HSP27 (an indirect target) and pMK2 (a directtarget).

p38α MAPK is known to play critical roles in skeletal muscle biology,specifically in abrogating proliferating myoblasts to differentiationand subsequently fusion to form multi-nucleated myotubes. Treatment ofmuscular dystrophy patients that are constitutively undergoing processesof degeneration and regeneration with p38α inhibitors would not beobvious. Complete knockout (KO) of p38α is embryonically lethal.Embryonic rescue allows for survival of pups to a few days postnatal andisolation of satellite cells to study Myogenic precursors lacking p38α.Myoblasts completely lacking p38α express significantly less criticaldifferentiation genes and show severe deficits in fusion. Histology ofP2 pups show significantly increased cycling satellite cells and aleft-shifted fiber distribution. (Perdiguero et. al, 2007). Importantly,KO of p38α in mature muscle (cre driven by Myl1 promoter) shows nodeficiencies in early time points, but mice deficient in p38α at 6months of age show significantly greater regeneration and type I fibers,as well as a smaller fiber distribution compared to controls (Wissinget. al, 2014). These data suggest that inhibition of p38α would triggerskeletal muscle regeneration in diseases deficient in regeneration inaddition to FSHD by a mechanism independent of regulation of DUX4expression.

In skeletal muscle, p38 has been shown to regulate gene expressionduring myogenesis. p38γ has been shown to be required for myogenesisusing both specific gene knock out and conditional knock out approaches(Cuenda et. al., 2007; Kerin et. al., 2006; Aouadi et. al., 2006). Inthe adult, selective inhibitors of p38α and β avoid p38γ-related impactto myogenesis.

The present disclosure finds that p38 is activated during myogenesis,and that inhibition of p38α and β by molecules exemplified herein,including FTX-839, FTX-1821, etc., profoundly reduces DUX4 expressionand its downstream gene program in FSHD myotubes (data exemplifiedherein). Without wishing to be bound by theory, p38α appears to directlyregulate DUX4 expression by impacting the activity of critical myogenicenhancers required for pathologic DUX4 expression at the level of themutated D4Z4 locus with shorter repeats (FSHD1) or SMCHD1 mutations(FSHD2) or when repression is lost by other mechanisms in the muscle ofFSHD patients. This is a differentiated mechanism from the previousclinical studies, which targeted functions of p38 in the cytoplasm andfailed to show efficacy in numerous diseases, including rheumatoidarthritis, pain, depression, chronic obstructive pulmonary disease, andcardiovascular disease. Inhibitors of p38 have never been exploredclinically for FSHD.

Definitions

As used in this specification and the appended claims, the singularforms “a,” “an” and “the” include plural references unless the contentclearly dictates otherwise.

As used in this specification, the term “and/or” is used in thisdisclosure to either “and” or “or” unless indicated otherwise.

Throughout this specification, unless the context requires otherwise,the word “comprise”, or variations such as “comprises” or “comprising”,will be understood to imply the inclusion of a stated element or integeror group of elements or integers but not the exclusion of any otherelement or integer or group of elements or integers.

As used in this application, the terms “about” and “approximately” areused as equivalents. Any numerals used in this application with orwithout about/approximately are meant to cover any normal fluctuationsappreciated by one of ordinary skill in the relevant art. In certainembodiments, the term “approximately” or “about” refers to a range ofvalues that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%,12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in eitherdirection (greater than or less than) of the stated reference valueunless otherwise stated or otherwise evident from the context (exceptwhere such number would exceed 100% of a possible value).

“Administration” refers herein to introducing an agent or compositioninto a subject or contacting an agent or composition with a cell and/ortissue.

“Treating” or “treatment” of a disease includes: (1) preventing thedisease, i.e., causing the clinical symptoms of the disease not todevelop in a mammal that may be exposed to or predisposed to the diseasebut does not yet experience or display symptoms of the disease; (2)inhibiting the disease, i.e., arresting or reducing the development ofthe disease or its clinical symptoms; or (3) relieving the disease,i.e., causing regression of the disease or its clinical symptoms.

“A therapeutically effective amount” means the amount of a compoundthat, when administered to a mammal for treating a disease, issufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the mammal tobe treated.

Certain compounds of the present invention may exist in stereoisomericforms (e.g. they may contain one or more asymmetric carbon atoms or mayexhibit cis-trans isomerism). Some compounds may include more than oneasymmetric carbon atoms. “Stereoisomer” refers to a compound that differin orientation (R/S) about one or more asymmetric carbon atom(s), ordiffers in orientation (cis:trans) about a double bond. The termstereoisomer may also encompass atropisomers, which arise from hinderedrotation about a single bond, e.g., in compounds having a substitutedbiphenyl moiety. An “enantiomer” is a compound that is a mirror image ofanother compound, i.e., all asymmetric carbon atoms of an enantiomerexist in opposite orientation (R/S) with respect to the other compound.A “diastereomer” is a compound that is not a mirror image of anothercompound, but includes one or more asymmetric carbon atoms existing inopposite orientation (R/S) with respect to the other compound. Theembodiments of the present invention may include mixtures ofstereoisomers, or may include a single stereoisomer. Single enantiomersor diastereomers may be prepared beginning with chiral reagents or bystereoselective or stereospecific synthetic techniques. Alternatively,the single enantiomers or diastereomers may be isolated from mixtures bystandard chiral chromatographic or crystallization techniques.

“Isotopically-enriched” refers to a compound wherein one or more atomsis enriched with an isotope beyond its natural abundance. For example,the natural abundance of deuterium is 0.015%. One of ordinary skill inthe art recognizes that in all chemical compounds with a H atom, the Hatom actually represents a mixture of H and D, with about 0.015% beingD. An isotopically-enriched compound may have one or more specificchemical sites wherein the H/D ratio is greater than 0.015%. Anisotopically-enriched compound may be referred to asisotopically-labeled.

“Solvate” refers to an aggregate of a compound with one or more solventmolecules—a complex of variable stoichiometry formed by a solute and thesolvent. Such solvents for the purpose of the invention may notinterfere with the biological activity of the solute. Examples ofsuitable solvents include water, methanol, ethanol and acetic acid.Preferably the solvent used is a pharmaceutically acceptable solvent.Examples of suitable pharmaceutically acceptable solvents include water,ethanol and acetic acid. All such solvates are included within the scopeof the present invention. For example, the solvent in any solvatedescribed herein may include water.

“Prodrug” refers to a compound that may be converted under physiologicalconditions or by solvolysis to the specified compound or to apharmaceutically acceptable salt of such compound.

“Pharmaceutically acceptable salt” is a salt that retains the biologicaleffectiveness of the free acids and bases of the specified compound andthat is not biologically or otherwise undesirable. A compound of theinvention may possess a sufficiently acidic, a sufficiently basic, orboth functional groups, and accordingly react with any of a number ofinorganic or organic bases, and inorganic and organic acids, to form apharmaceutically acceptable sale. Examples of pharmaceuticallyacceptable salts include those salts prepared by reaction of thecompounds of the present invention with a mineral or organic acid or aninorganic base. For example, salts of the present invention include, butare not limited to: sulfates, pyrosulfates, bisulfates, sulfites,bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates,metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates,propionates, decanoates, caprylates, acrylates, formates, iso-butyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyn-1,4-dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates,dinitro-menzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, xylenesulfonates, pheylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycollates,tartrates, methanesulfonates, propanesulfonates,naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates. Forexample, salts of the present invention include, but are not limited to:Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate,Borate, Bromide, Calcium Edetate, Camsylate, Carbonate, Chloride,Clavulanate, Citrate, Dihydrochloride, Edetate, Edisylate, Estolate,Esylate, Fumarate, Gluceptate, Gluconate, Glutamate,Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide,Hydrochloride, Hydroxynaphthoate, Iodide, Isethionate, Lactate,Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate,Methylbromide, Methylnitrate, Methylsulfate, Monopotassium Maleate,Mucate, Napsylate, Nitrate, N-methylglucamine, Oxalate, Parnoate(Embonate), Palmitate, Pantothenate, Phosphate/diphosphate,Polygalacturonate, Potassium, Salicylate, Sodium, Stearate, Subacetate,Succinate, Tannate, Tartrate, Teoclate, Tosylate, Triethiodide,Trimethylammonium and Valerate. For example, salts of the presentinvention include, but are not limited to: hydrochloric, sulfuric,phosphoric, diphosphoric, hydrobromic, and nitric or salts of organicacids such as formic, citric, malic, maleic, fumaric, tartaric,succinic, acetic, lactic, methanesulfonic, p-toluenesulfonic,2-hydroxyethylsulfonic, salicylic and stearic. Similarly,pharmaceutically acceptable cations include, but are not limited tosodium, potassium, calcium, aluminum, lithium and ammonium. For example,salts of the present invention include, but are not limited to: alkalimetal salts: sodium salt, potassium salt and the like; alkaline earthmetal salt: calcium salt, magnesium salt, barium salt, and the like;aluminum salt and the like. As a suitable example of a salt with anorganic base, for example, there are salts with trimethylamine,triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine,diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine,N,N′-dibenzylethylenediamine and the like. As a suitable example of asalt with an inorganic acid, for example, there are salts withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid and the like. As a suitable example of a salt with anorganic acid, for example, there are salts with formic acid, aceticacid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid,tartaric acid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid andthe like. As a suitable example of a salt with a basic amino acid, forexample, there are salts with alginine, lysine, ornithine and the like.As a suitable example of a salt with an acidic amino acid, for example,there are salts with aspartic acid, glutamic acid and the like.

Methods of Use

In several embodiments, a method for treating a disorder responsive top38 kinase inhibition is provided. The method may include administeringto a subject in need thereof, an effective amount of a p38 kinaseinhibitor selected from one or more of the following Formulae I′-XXIX′:

or a stereoisomer thereof, an isotopically-enriched compound thereof, aprodrug thereof, a solvate thereof, or a pharmaceutically acceptablesalt thereof. The method includes the treatment of disorders associatedwith DUX4 gene expression, wherein the inhibition of p38 kinase with ap38 kinase inhibitor may reduce DUX4 expression levels and/or theexpression of one or more downstream genes in cells of the subject.

In some embodiments, the p38 kinase inhibitor is a compound selectedfrom Formulae I′-XXIX′, or a stereoisomer thereof, anisotopically-enriched compound thereof, a prodrug thereof, a solvatethereof, or a pharmaceutically acceptable salt thereof.

In some embodiments, the p38 kinase inhibitor is selected from FormulaeI′, II′, III′a, III′b, and IV′-XIV′, or a stereoisomer thereof, anisotopically-enriched compound thereof, a prodrug thereof, a solvatethereof, or a pharmaceutically acceptable salt thereof.

In some embodiments, the p38 kinase inhibitor is selected from FormulaeI′, II′, IV′-VIII′, and X′-XIII′, or a stereoisomer thereof, anisotopically-enriched compound thereof, a prodrug thereof, a solvatethereof, or a pharmaceutically acceptable salt thereof.

In one embodiment, the p38 kinase inhibitor is a compound of Formula I′,or a stereoisomer thereof, an isotopically-enriched compound thereof, aprodrug thereof, a solvate thereof, or a pharmaceutically acceptablesalt thereof.

In one embodiment, the p38 kinase inhibitor is a compound of FormulaII′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the p38 kinase inhibitor is a compound of FormulaIIIa′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the p38 kinase inhibitor is a compound of FormulaIIIb′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the p38 kinase inhibitor is a compound of FormulaIV′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the p38 kinase inhibitor is a compound of Formula V′,or a stereoisomer thereof, an isotopically-enriched compound thereof, aprodrug thereof, a solvate thereof, or a pharmaceutically acceptablesalt thereof.

In one embodiment, the p38 kinase inhibitor is a compound of FormulaVI′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the p38 kinase inhibitor is a compound of FormulaVII′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the p38 kinase inhibitor is a compound of FormulaVIII′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the p38 kinase inhibitor is a compound of FormulaIX′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the p38 kinase inhibitor is a compound of Formula X′,or a stereoisomer thereof, an isotopically-enriched compound thereof, aprodrug thereof, a solvate thereof, or a pharmaceutically acceptablesalt thereof.

In one embodiment, the p38 kinase inhibitor is a compound of FormulaXI′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the p38 kinase inhibitor is a compound of FormulaXII′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the p38 kinase inhibitor is a compound of FormulaXIII′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the p38 kinase inhibitor is a compound of FormulaXIV′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the p38 kinase inhibitor is a compound of FormulaXV′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the p38 kinase inhibitor is a compound of FormulaXVI′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the p38 kinase inhibitor is a compound of FormulaXVII′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the p38 kinase inhibitor is a compound of FormulaXVIII′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the p38 kinase inhibitor is a compound of FormulaXIX′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the p38 kinase inhibitor is a compound of FormulaXX′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the p38 kinase inhibitor is a compound of FormulaXXI′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the p38 kinase inhibitor is a compound of FormulaXXII′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the p38 kinase inhibitor is a compound of FormulaXXIII′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the p38 kinase inhibitor is a compound of FormulaXXIV′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the p38 kinase inhibitor is a compound of FormulaXXV′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the p38 kinase inhibitor is a compound of FormulaXXVI′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the p38 kinase inhibitor is a compound of FormulaXXVII′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the p38 kinase inhibitor is a compound of FormulaXXVIII′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the p38 kinase inhibitor is a compound of FormulaXXIX′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In many embodiments, the cells are muscle cells. In some embodiments,the cells are terminally-differentiated muscle cells.

In some embodiments, the cells include one or more mutations in aStructural Maintenance Of Chromosomes Flexible Hinge Domain Containing 1(SMCHD1) gene. In some embodiments, the cells may include at least onenon-deleted 4qA allele.

In many embodiments, the cells may include an increased expression levelof a DUX4 polypeptide, or a polypeptide encoded by one or moredownstream target genes, as compared to the expression level of a DUX4polypeptide, or a polypeptide encoded by one or more downstream targetgenes in a control cell.

In many embodiments, the DUX4 is a DUX4 full length (DUX4-fl).

In some embodiments, the cells may be associated with FSHD.

In some embodiments, the disorder is associated with DUX4 geneexpression.

In some embodiments, the disorder is associated with DUX4 geneexpression and the DUX4 gene expression may result from the subjecthaving less than 10 D4Z4 repeats in the subtelomeric region ofchromosome 4q35. In some embodiments, the cells may include a deletionof one or more macrosatellite D4Z4 repeats in the subtelomeric region ofchromosome 4q35. In other embodiments, the cells may include less than 7macrosatellite D4Z4 repeats in the subtelomeric region of chromosome4q35.

In some embodiments, the cells may include a dysregulated D4Z4 array atchromosome 4q35 prior to administration of the p38 kinase inhibitor. Inone embodiment, the cells may include a dysregulated D4Z4 arrayincluding fewer than 11 repeat units. In some embodiments, thedysregulated D4Z4 array may include fewer than 11, 10, 9, 8, 7, 6, 5, 4,3, or 2 repeat units.

In some embodiments, the cells are muscle cells and the cells mayinclude a dysregulated D4Z4 array at chromosome 4q35 prior toadministration of the p38 kinase inhibitor. In one embodiment, themuscles cells may include a dysregulated D4Z4 array including fewer than11 repeat units. In some embodiments, the dysregulated D4Z4 array mayinclude fewer than 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 repeat units.

In some embodiments, the disorder is FSHD. FSHD may include one or moreof FSHD1 and FSHD2. In one embodiment, the disorder is FSHD1. In anotherembodiment, the disorder is FSHD2. In one embodiment, the disorder isFSHD1 and FSHD2.

In one embodiment, the disorder is ICF (immunodeficiency, centromericregion instability and facial anomalies).

In one embodiment, the disorder is amyotrophic lateral sclerosis (ALS).

In one embodiment, the disorder is inclusion body myopathy (IBM).

In one embodiment, the disorder is cancer. The cancer may be selectedfrom Ewing's sarcoma, soft tissue sarcoma, rhabdomyosarcoma, and adultand pediatric B-cell acute lymphoblastic leukemia.

In some embodiments, the disorder may be selected from one or more of:FSHD1, FSHD2, ICF, ALS, IBM, Ewing's sarcoma, soft tissue sarcoma,rhabdomyosarcoma, and adult and pediatric B-cell acute lymphoblasticleukemia.

In one embodiment, the subject is identified as having FSHD based uponthe presence of a transcriptionally active DUX4. In another embodiment,the subject is identified as having FSHD based upon the presence of oneor more downstream genes ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2, KHDC1L,RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6,PRAMEF15, and ZNF280A in muscle. In another embodiment, the subject isidentified as having FSHD based upon the presence of increasedexpression levels of one or more downstream genes ZSCAN4, LEUTX,PRAMEF2, TRIM43, MBD3L2, KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20,TRIM49, PRAMEF4, PRAME6, PRAMEF15, and ZNF280A relative to a healthycontrol. In another embodiment, the subject is identified as having FSHDbased upon the presence of a transcriptionally active DUX4 and thepresence of downstream genes ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2,KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6,PRAMEF15, or ZNF280A.

In another embodiment, the method may include measuring the expressionlevel of one or more of: DUX4, ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2,KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6,PRAMEF15, and ZNF280A in the subject prior to the administration of thep38 kinase inhibitor. The method may further include determining thatthe subject is in need of treatment if the expression level of one ormore of: DUX4, ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2, KHDC1L, RFPL2,CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6, PRAMEF15, andZNF280A is/are elevated relative to a healthy control.

In another embodiment, the method may include measuring the expressionlevel of one or more of: DUX4, ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2,KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6,PRAMEF15, and ZNF280A in the cells of the subject before and after theadministration of the p38 kinase inhibitor. The method may includecomparing the expression level of one or more of: DUX4, ZSCAN4, LEUTX,PRAMEF2, TRIM43, MBD3L2, KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20,TRIM49, PRAMEF4, PRAME6, PRAMEF15, and ZNF280A in the subject before andafter the administration of the p38 kinase inhibitor. The method mayinclude determining the effectiveness of treatment by the comparing ofthe expression level of one or more of: DUX4, ZSCAN4, LEUTX, PRAMEF2,TRIM43, MBD3L2, KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49,PRAMEF4, PRAME6, PRAMEF15, and ZNF280A before and after theadministration of the p38 kinase inhibitor, wherein a decrease in theexpression level(s) is indicative of effective treatment.

In some embodiments, the p38 kinase inhibitor reduces one or moredownstream genes selected from ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2,KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6,PRAMEF15, and ZNF280A.

In one embodiment, the p38 kinase inhibitor reduces MBD3L2.

In one embodiment, the p38 kinase inhibitor reduces ZSCAN4.

In one embodiment, the p38 kinase inhibitor reduces LEUTX.

In one embodiment, the p38 kinase inhibitor reduces PRAMEF2.

In one embodiment, the p38 kinase inhibitor reduces TRIM43.

In one embodiment, the p38 kinase inhibitor reduces KHDC1L.

In one embodiment, a transcriptional modulator of DUX4 and downstreamgenes ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2, KHDC1L, RFPL2, CCNA1,SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6, PRAMEF15, and ZNF280Aare inhibited by p38 kinase.

In some embodiments, the administering may be combined with clinicalmanagement involving physical therapy, aerobic exercise, respiratoryfunction therapy, orthopedic interventions.

In some embodiments, the administering includes administering of the p38kinase inhibitor with another pharmaceutical agent.

In some embodiments, the administering includes administering of the p38kinase inhibitor with another pharmaceutical agent for the treatment ofFSHD.

In some embodiments, the administering causes a decrease in muscledegeneration.

In some embodiments, the administering causes a reduction in apoptosisof muscle cells in the subject. In one embodiment, the muscles cells areterminally differentiated.

In several embodiments, a method for treating facioscapulohumeralmuscular dystrophy (FSHD) is provided. The method may includeadministering to a subject in need thereof, an effective amount of a p38kinase inhibitor selected from one or more of Formulae I′-XXIX′, or astereoisomer thereof, an isotopically-enriched compound thereof, aprodrug thereof, a solvate thereof, or a pharmaceutically acceptablesalt thereof.

In some embodiments, the p38 kinase inhibitor is selected from FormulaeI′-XXIX′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the p38 kinase inhibitor is selected from FormulaeI′, II′, III′a, III′b, and IV′-XIV′, or a stereoisomer thereof, anisotopically-enriched compound thereof, a prodrug thereof, a solvatethereof, or a pharmaceutically acceptable salt thereof.

In some embodiments, the p38 kinase inhibitor is selected from FormulaeI′, II′, IV′-VIII′, and X′-XIII′, or a stereoisomer thereof, anisotopically-enriched compound thereof, a prodrug thereof, a solvatethereof, or a pharmaceutically acceptable salt thereof.

In one embodiment, the p38 kinase inhibitor may include a compound ofFormula I′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the p38 kinase inhibitor may include a compound ofFormula II′, or a stereoisomer thereof, an isotopically-enrichedcompound thereof, a prodrug thereof, a solvate thereof, or apharmaceutically acceptable salt thereof.

In one embodiment, the p38 kinase inhibitor may include a compound ofFormula IIIa′, or a stereoisomer thereof, an isotopically-enrichedcompound thereof, a prodrug thereof, a solvate thereof, or apharmaceutically acceptable salt thereof.

In one embodiment, the p38 kinase inhibitor may include a compound ofFormula IIIb′, or a stereoisomer thereof, an isotopically-enrichedcompound thereof, a prodrug thereof, a solvate thereof, or apharmaceutically acceptable salt thereof.

In one embodiment, the p38 kinase inhibitor may include a compound ofFormula IV′, or a stereoisomer thereof, an isotopically-enrichedcompound thereof, a prodrug thereof, a solvate thereof, or apharmaceutically acceptable salt thereof.

In one embodiment, the p38 kinase inhibitor may include a compound ofFormula V′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the p38 kinase inhibitor may include a compound ofFormula VI′, or a stereoisomer thereof, an isotopically-enrichedcompound thereof, a prodrug thereof, a solvate thereof, or apharmaceutically acceptable salt thereof.

In one embodiment, the p38 kinase inhibitor may include a compound ofFormula VII′, or a stereoisomer thereof, an isotopically-enrichedcompound thereof, a prodrug thereof, a solvate thereof, or apharmaceutically acceptable salt thereof.

In one embodiment, the p38 kinase inhibitor may include a compound ofFormula VIII′, or a stereoisomer thereof, an isotopically-enrichedcompound thereof, a prodrug thereof, a solvate thereof, or apharmaceutically acceptable salt thereof.

In one embodiment, the p38 kinase inhibitor may include a compound ofFormula IX′, or a stereoisomer thereof, an isotopically-enrichedcompound thereof, a prodrug thereof, a solvate thereof, or apharmaceutically acceptable salt thereof.

In one embodiment, the p38 kinase inhibitor may include a compound ofFormula X′, or a stereoisomer thereof, an isotopically-enriched compoundthereof, a prodrug thereof, a solvate thereof, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the p38 kinase inhibitor may include a compound ofFormula XI′, or a stereoisomer thereof, an isotopically-enrichedcompound thereof, a prodrug thereof, a solvate thereof, or apharmaceutically acceptable salt thereof.

In one embodiment, the p38 kinase inhibitor may include a compound ofFormula XII′, or a stereoisomer thereof, an isotopically-enrichedcompound thereof, a prodrug thereof, a solvate thereof, or apharmaceutically acceptable salt thereof.

In one embodiment, the p38 kinase inhibitor may include a compound ofFormula XIII′, or a stereoisomer thereof, an isotopically-enrichedcompound thereof, a prodrug thereof, a solvate thereof, or apharmaceutically acceptable salt thereof.

In one embodiment, the p38 kinase inhibitor may include a compound ofFormula XIV′, or a stereoisomer thereof, an isotopically-enrichedcompound thereof, a prodrug thereof, a solvate thereof, or apharmaceutically acceptable salt thereof.

In one embodiment, the p38 kinase inhibitor may include a compound ofFormula XV′, or a stereoisomer thereof, an isotopically-enrichedcompound thereof, a prodrug thereof, a solvate thereof, or apharmaceutically acceptable salt thereof.

In one embodiment, the p38 kinase inhibitor may include a compound ofFormula XVI′, or a stereoisomer thereof, an isotopically-enrichedcompound thereof, a prodrug thereof, a solvate thereof, or apharmaceutically acceptable salt thereof.

In one embodiment, the p38 kinase inhibitor may include a compound ofFormula XVII′, or a stereoisomer thereof, an isotopically-enrichedcompound thereof, a prodrug thereof, a solvate thereof, or apharmaceutically acceptable salt thereof.

In one embodiment, the p38 kinase inhibitor may include a compound ofFormula XVIII′, or a stereoisomer thereof, an isotopically-enrichedcompound thereof, a prodrug thereof, a solvate thereof, or apharmaceutically acceptable salt thereof.

In one embodiment, the p38 kinase inhibitor may include a compound ofFormula XIX′, or a stereoisomer thereof, an isotopically-enrichedcompound thereof, a prodrug thereof, a solvate thereof, or apharmaceutically acceptable salt thereof.

In one embodiment, the p38 kinase inhibitor may include a compound ofFormula XX′, or a stereoisomer thereof, an isotopically-enrichedcompound thereof, a prodrug thereof, a solvate thereof, or apharmaceutically acceptable salt thereof.

In one embodiment, the p38 kinase inhibitor may include a compound ofFormula XXI′, or a stereoisomer thereof, an isotopically-enrichedcompound thereof, a prodrug thereof, a solvate thereof, or apharmaceutically acceptable salt thereof.

In one embodiment, the p38 kinase inhibitor may include a compound ofFormula XXII′, or a stereoisomer thereof, an isotopically-enrichedcompound thereof, a prodrug thereof, a solvate thereof, or apharmaceutically acceptable salt thereof.

In one embodiment, the p38 kinase inhibitor may include a compound ofFormula XXIII′, or a stereoisomer thereof, an isotopically-enrichedcompound thereof, a prodrug thereof, a solvate thereof, or apharmaceutically acceptable salt thereof.

In one embodiment, the p38 kinase inhibitor may include a compound ofFormula XXIV′, or a stereoisomer thereof, an isotopically-enrichedcompound thereof, a prodrug thereof, a solvate thereof, or apharmaceutically acceptable salt thereof.

In one embodiment, the p38 kinase inhibitor may include a compound ofFormula XXV′, or a stereoisomer thereof, an isotopically-enrichedcompound thereof, a prodrug thereof, a solvate thereof, or apharmaceutically acceptable salt thereof.

In one embodiment, the p38 kinase inhibitor may include a compound ofFormula XXVI′, or a stereoisomer thereof, an isotopically-enrichedcompound thereof, a prodrug thereof, a solvate thereof, or apharmaceutically acceptable salt thereof.

In one embodiment, the p38 kinase inhibitor may include a compound ofFormula XXVII′, or a stereoisomer thereof, an isotopically-enrichedcompound thereof, a prodrug thereof, a solvate thereof, or apharmaceutically acceptable salt thereof.

In one embodiment, the p38 kinase inhibitor may include a compound ofFormula XXVIII′, or a stereoisomer thereof, an isotopically-enrichedcompound thereof, a prodrug thereof, a solvate thereof, or apharmaceutically acceptable salt thereof.

In one embodiment, the p38 kinase inhibitor may include a compound ofFormula XXIX′, or a stereoisomer thereof, an isotopically-enrichedcompound thereof, a prodrug thereof, a solvate thereof, or apharmaceutically acceptable salt thereof.

In some embodiments, the disorder is FSHD. FSHD may include one or moreof FSHD1 and FSHD2. In one embodiment, the disorder is FSHD1. In anotherembodiment, the disorder is FSHD2. In one embodiment, the disorder isFSHD1 and FSHD2.

In several embodiments, a method for treating a disorder responsive top38 kinase inhibition is provided. The method may include administeringto a subject in need thereof, an effective amount of a p38 kinaseinhibitor of Formula V′:

or a stereoisomer thereof, an isotopically-enriched compound thereof, aprodrug thereof, a solvate thereof, or a pharmaceutically acceptablesalt thereof. The method includes the treatment of disorders associatedwith DUX4 gene expression, wherein the inhibition of p38 kinase with ap38 kinase inhibitor may reduce DUX4 expression levels and/or theexpression of one or more downstream genes in cells of the subject.

In many embodiments, the cells are muscle cells. In some embodiments,the cells are terminally-differentiated muscle cells.

In some embodiments, the cells include one or more mutations in aStructural Maintenance Of Chromosomes Flexible Hinge Domain Containing 1(SMCHD1) gene. In some embodiments, the cells may include at least onenon-deleted 4qA allele.

In many embodiments, the cells may include an increased expression levelof a DUX4 polypeptide, or a polypeptide encoded by one or moredownstream target genes, as compared to the expression level of a DUX4polypeptide, or a polypeptide encoded by one or more downstream targetgenes in a control cell.

In many embodiments, the DUX4 is a DUX4 full length (DUX4-fl).

In some embodiments, the cells may be associated with FSHD.

In some embodiments, the disorder is associated with DUX4 geneexpression.

In some embodiments, the disorder is associated with DUX4 geneexpression and the DUX4 gene expression may result from the subjecthaving less than 10 D4Z4 repeats in the subtelomeric region ofchromosome 4q35. In some embodiments, the cells may include a deletionof one or more macrosatellite D4Z4 repeats in the subtelomeric region ofchromosome 4q35. In other embodiments, the cells may include less than 7macrosatellite D4Z4 repeats in the subtelomeric region of chromosome4q35.

In some embodiments, the cells may include a dysregulated D4Z4 array atchromosome 4q35 prior to administration of the p38 kinase inhibitor. Inone embodiment, the cells may include a dysregulated D4Z4 arrayincluding fewer than 11 repeat units. In some embodiments, thedysregulated D4Z4 array may include fewer than 11, 10, 9, 8, 7, 6, 5, 4,3, or 2 repeat units.

In some embodiments, the cells are muscle cells and the cells mayinclude a dysregulated D4Z4 array at chromosome 4q35 prior toadministration of the p38 kinase inhibitor. In one embodiment, themuscles cells may include a dysregulated D4Z4 array including fewer than11 repeat units. In some embodiments, the dysregulated D4Z4 array mayinclude fewer than 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 repeat units.

In some embodiments, the disorder is FSHD. FSHD may include one or moreof FSHD1 and FSHD2. In one embodiment, the disorder is FSHD1. In anotherembodiment, the disorder is FSHD2. In one embodiment, the disorder isFSHD1 and FSHD2.

In one embodiment, the disorder is ICF.

In one embodiment, the disorder is ALS.

In one embodiment, the disorder is IBM.

In one embodiment, the disorder is cancer. The cancer may be selectedfrom Ewing's sarcoma, soft tissue sarcoma, rhabdomyosarcoma, and adultand pediatric B-cell acute lymphoblastic leukemia.

In some embodiments, the disorder may be selected from one or more of:FSHD1, FSHD2, ICF, ALS, IBM, Ewing's sarcoma, soft tissue sarcoma,rhabdomyosarcoma, and adult and pediatric B-cell acute lymphoblasticleukemia.

In one embodiment, the subject is identified as having FSHD based uponthe presence of a transcriptionally active DUX4. In another embodiment,the subject is identified as having FSHD based upon the presence of oneor more downstream genes ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2, KHDC1L,RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6,PRAMEF15, and ZNF280A in muscle. In another embodiment, the subject isidentified as having FSHD based upon the presence of increasedexpression levels of one or more downstream genes ZSCAN4, LEUTX,PRAMEF2, TRIM43, MBD3L2, KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20,TRIM49, PRAMEF4, PRAME6, PRAMEF15, and ZNF280A relative to a healthycontrol. In another embodiment, the subject is identified as having FSHDbased upon the presence of a transcriptionally active DUX4 and thepresence of one or more downstream genes ZSCAN4, LEUTX, PRAMEF2, TRIM43,MBD3L2, KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4,PRAME6, PRAMEF15, and ZNF280A.

In another embodiment, the method may include measuring the expressionlevel of one or more of: DUX4, ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2,KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6,PRAMEF15, and ZNF280A in the subject prior to the administration of thep38 kinase inhibitor. The method may further include determining thatthe subject is in need of treatment if the expression level of one ormore of: DUX4, ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2, KHDC1L, RFPL2,CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6, PRAMEF15, andZNF280A is/are elevated relative to a healthy control.

In another embodiment, the method may include measuring the expressionlevel of one or more of: DUX4, ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2,KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6,PRAMEF15, and ZNF280A in the cells of the subject before and after theadministration of the p38 kinase inhibitor. The method may includecomparing the expression level of one or more of: DUX4, ZSCAN4, LEUTX,PRAMEF2, TRIM43, MBD3L2, KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20,TRIM49, PRAMEF4, PRAME6, PRAMEF15, and ZNF280A in the subject before andafter the administration of the p38 kinase inhibitor. The method mayinclude determining the effectiveness of treatment by the comparing ofthe expression level of one or more of: DUX4, ZSCAN4, LEUTX, PRAMEF2,TRIM43, MBD3L2, KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49,PRAMEF4, PRAME6, PRAMEF15, and ZNF280A before and after theadministration of the p38 kinase inhibitor, wherein a decrease in theexpression level(s) is indicative of effective treatment.

In some embodiments, the p38 kinase inhibitor reduces one or moredownstream genes selected from ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2,KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6,PRAMEF15, and ZNF280A.

In one embodiment, the p38 kinase inhibitor reduces MBD3L2.

In one embodiment, the p38 kinase inhibitor reduces ZSCAN4.

In one embodiment, the p38 kinase inhibitor reduces LEUTX.

In one embodiment, the p38 kinase inhibitor reduces PRAMEF2.

In one embodiment, the p38 kinase inhibitor reduces TRIM43.

In one embodiment, the p38 kinase inhibitor reduces KHDC1L.

In one embodiment, a transcriptional modulator of DUX4 and downstreamgenes ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2, KHDC1L, RFPL2, CCNA1,SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6, PRAMEF15, and ZNF280Aare inhibited by p38 kinase.

In some embodiments, the administering may be combined with clinicalmanagement involving physical therapy, aerobic exercise, respiratoryfunction therapy, orthopedic interventions.

In some embodiments, the administering includes administering of the p38kinase inhibitor with another pharmaceutical agent.

In some embodiments, the administering includes administering of the p38kinase inhibitor with another pharmaceutical agent for the treatment ofFSHD.

In some embodiments, the administering causes a decrease in muscledegeneration.

In some embodiments, the administering causes a reduction in apoptosisof muscle cells in the subject. In one embodiment, the muscles cells areterminally differentiated.

In several embodiments, a method for treating facioscapulohumeralmuscular dystrophy (FSHD) is provided. The method may includeadministering to a subject in need thereof, an effective amount of a p38kinase inhibitor of Formula V′:

or a stereoisomer thereof, an isotopically-enriched compound thereof, aprodrug thereof, a solvate thereof, or a pharmaceutically acceptablesalt thereof.

In some embodiments, the disorder is FSHD. FSHD may include one or moreof FSHD1 and FSHD2. In one embodiment, the disorder is FSHD1. In anotherembodiment, the disorder is FSHD2. In one embodiment, the disorder isFSHD1 and FSHD2.

In several embodiments, a method for treating a disorder responsive top38 kinase inhibition is provided. The method may include administeringto a subject in need thereof, an effective amount of a p38 kinaseinhibitor selected from one or more of Formulae I-XIII (of GenusesI-XIII described below), or a stereoisomer thereof, anisotopically-enriched compound thereof, a prodrug thereof, a solvatethereof, or a pharmaceutically acceptable salt thereof. The methodincludes the treatment of disorders associated with DUX4 geneexpression, wherein the inhibition of p38 kinase with a p38 kinaseinhibitor may reduce DUX4 expression levels and/or the expression of oneor more downstream genes in cells of the subject.

In many embodiments, the cells are muscle cells. In some embodiments,the cells are terminally-differentiated muscle cells.

In some embodiments, the cells include one or more mutations in aStructural Maintenance Of Chromosomes Flexible Hinge Domain Containing 1(SMCHD1) gene. In some embodiments, the cells may include at least onenon-deleted 4qA allele.

In many embodiments, the cells may include an increased expression levelof a DUX4 polypeptide, or a polypeptide encoded by one or moredownstream target genes, as compared to the expression level of a DUX4polypeptide, or a polypeptide encoded by one or more downstream targetgenes in a control cell.

In many embodiments, the DUX4 is a DUX4 full length (DUX4-fl).

In some embodiments, the cells may be associated with FSHD.

In some embodiments, the disorder is associated with DUX4 geneexpression.

In some embodiments, the disorder is associated with DUX4 geneexpression and the DUX4 gene expression may result from the subjecthaving less than 10 D4Z4 repeats in the subtelomeric region ofchromosome 4q35. In some embodiments, the cells may include a deletionof one or more macrosatellite D4Z4 repeats in the subtelomeric region ofchromosome 4q35. In other embodiments, the cells may include less than 7macrosatellite D4Z4 repeats in the subtelomeric region of chromosome4q35.

In some embodiments, the cells may include a dysregulated D4Z4 array atchromosome 4q35 prior to administration of the p38 kinase inhibitor. Inone embodiment, the cells may include a dysregulated D4Z4 arrayincluding fewer than 11 repeat units. In some embodiments, thedysregulated D4Z4 array may include fewer than 11, 10, 9, 8, 7, 6, 5, 4,3, or 2 repeat units.

In some embodiments, the cells are muscle cells and the cells mayinclude a dysregulated D4Z4 array at chromosome 4q35 prior toadministration of the p38 kinase inhibitor. In one embodiment, themuscles cells may include a dysregulated D4Z4 array including fewer than11 repeat units. In some embodiments, the dysregulated D4Z4 array mayinclude fewer than 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 repeat units.

In some embodiments, the disorder is FSHD. FSHD may include one or moreof FSHD1 and FSHD2. In one embodiment, the disorder is FSHD1. In anotherembodiment, the disorder is FSHD2. In one embodiment, the disorder isFSHD1 and FSHD2.

In one embodiment, the disorder is ICF.

In one embodiment, the disorder is ALS.

In one embodiment, the disorder is IBM.

In one embodiment, the disorder is cancer. The cancer may be selectedfrom Ewing's sarcoma, soft tissue sarcoma, rhabdomyosarcoma, and adultand pediatric B-cell acute lymphoblastic leukemia.

In some embodiments, the disorder may be selected from one or more of:FSHD1, FSHD2, ICF, ALS, IBM, Ewing's sarcoma, soft tissue sarcoma,rhabdomyosarcoma, and adult and pediatric B-cell acute lymphoblasticleukemia.

In one embodiment, the subject is identified as having FSHD based uponthe presence of a transcriptionally active DUX4. In another embodiment,the subject is identified as having FSHD based upon the presence of oneor more downstream genes ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2, KHDC1L,RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6,PRAMEF15, and ZNF280A in muscle. In another embodiment, the subject isidentified as having FSHD based upon the presence of increasedexpression levels of one or more downstream genes ZSCAN4, LEUTX,PRAMEF2, TRIM43, MBD3L2, KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20,TRIM49, PRAMEF4, PRAME6, PRAMEF15, and ZNF280A relative to a healthycontrol. In another embodiment, the subject is identified as having FSHDbased upon the presence of a transcriptionally active DUX4 and thepresence of one or more downstream genes ZSCAN4, LEUTX, PRAMEF2, TRIM43,MBD3L2, KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4,PRAME6, PRAMEF15, and ZNF280A.

In another embodiment, the method may include measuring the expressionlevel of one or more of: DUX4, ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2,KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6,PRAMEF15, and ZNF280A in the subject prior to the administration of thep38 kinase inhibitor. The method may further include determining thatthe subject is in need of treatment if the expression level of one ormore of: DUX4, ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2, KHDC1L, RFPL2,CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6, PRAMEF15, andZNF280A is/are elevated relative to a healthy control.

In another embodiment, the method may include measuring the expressionlevel of one or more of: DUX4, ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2,KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6,PRAMEF15, and ZNF280A in the cells of the subject before and after theadministration of the p38 kinase inhibitor. The method may includecomparing the expression level of one or more of: DUX4, ZSCAN4, LEUTX,PRAMEF2, TRIM43, MBD3L2, KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20,TRIM49, PRAMEF4, PRAME6, PRAMEF15, and ZNF280A in the subject before andafter the administration of the p38 kinase inhibitor. The method mayinclude determining the effectiveness of treatment by the comparing ofthe expression level of one or more of: DUX4, ZSCAN4, LEUTX, PRAMEF2,TRIM43, MBD3L2, KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49,PRAMEF4, PRAME6, PRAMEF15, and ZNF280A before and after theadministration of the p38 kinase inhibitor, wherein a decrease in theexpression level(s) is indicative of effective treatment.

In some embodiments, the p38 kinase inhibitor reduces one or moredownstream genes selected from ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2,KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6,PRAMEF15, and ZNF280A.

In one embodiment, the p38 kinase inhibitor reduces MBD3L2.

In one embodiment, the p38 kinase inhibitor reduces ZSCAN4.

In one embodiment, the p38 kinase inhibitor reduces LEUTX.

In one embodiment, the p38 kinase inhibitor reduces PRAMEF2.

In one embodiment, the p38 kinase inhibitor reduces TRIM43.

In one embodiment, the p38 kinase inhibitor reduces KHDC1L.

In one embodiment, a transcriptional modulator of DUX4 and downstreamgenes ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2, KHDC1L, RFPL2, CCNA1,SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6, PRAMEF15, and ZNF280Aare inhibited by p38 kinase.

In some embodiments, the administering may be combined with clinicalmanagement involving physical therapy, aerobic exercise, respiratoryfunction therapy, orthopedic interventions.

In some embodiments, the administering includes administering of the p38kinase inhibitor with another pharmaceutical agent.

In some embodiments, the administering includes administering of the p38kinase inhibitor with another pharmaceutical agent for the treatment ofFSHD.

In some embodiments, the administering causes a decrease in muscledegeneration.

In some embodiments, the administering causes a reduction in apoptosisof muscle cells in the subject. In one embodiment, the muscles cells areterminally differentiated.

In several embodiments, a method for treating facioscapulohumeralmuscular dystrophy (FSHD) is provided. The method may includeadministering to a subject in need thereof, an effective amount of a p38kinase inhibitor selected from one or more of Formulae I-XIII (ofGenuses I-XIII described below), or a stereoisomer thereof, anisotopically-enriched compound thereof, a prodrug thereof, a solvatethereof, or a pharmaceutically acceptable salt thereof.

In some embodiments, the p38 kinase inhibitor is selected from one ormore of Genuses I-XIII characterized by Formulae I-XIII Each chemicalidentifier, e.g., R¹, R², X, Z, and the like, is unique to the Genusunder which it is described. Likewise, each definition of any suchchemical identifiers or chemical nomenclature terms, e.g., aryl,heteroaryl, alkynyl, and the like, are unique to the Genus under whichit is described. If any such chemical nomenclature term is notspecifically defined for a particular Genus, the term shall be construedto involve the definition understood by a person of ordinary skill inthe art.

In one embodiment, the p38 kinase inhibitor is selected from Genus I,II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, and XIII, or anycombination thereof. For example, the p38 kinase inhibitor may beselected from Genus I, II and III. For example, the p38 kinase inhibitormay be selected from Genus III and V.

In one embodiment, the p38 kinase inhibitor is selected from Genus I.

In one embodiment, the p38 kinase inhibitor is selected from Genus II.

In one embodiment, the p38 kinase inhibitor is selected from Genus III.

In one embodiment, the p38 kinase inhibitor is selected from Genus IV.

In one embodiment, the p38 kinase inhibitor is selected from Genus V.

In one embodiment, the p38 kinase inhibitor is selected from Genus VI.

In one embodiment, the p38 kinase inhibitor is selected from Genus VII.

In one embodiment, the p38 kinase inhibitor is selected from Genus VIII.

In one embodiment, the p38 kinase inhibitor is selected from Genus IX.

In one embodiment, the p38 kinase inhibitor is selected from Genus X.

In one embodiment, the p38 kinase inhibitor is selected from Genus XI.

In one embodiment, the p38 kinase inhibitor is selected from Genus XII.

In one embodiment, the p38 kinase inhibitor is selected from Genus XIII

In one embodiment, the p38 kinase inhibitor is selected from Genus I,II, III, V, VI, VII, VIII, X, XI, XII, and XIII

Genus I Description

Compounds of Genus I can be prepared according to the disclosure of U.S.Pat. No. 7,276,527, which is herein incorporated herein by reference inits entirety.

Genus I is characterized by optionally N-oxidized compounds of Formula(I):

or stereoisomers thereof, isotopically-enriched compounds thereof,prodrugs thereof, solvates thereof, and pharmaceutically acceptablesalts thereof;wherein:

-   R¹ is selected from:    -   (i) hydrogen,    -   (ii) a group selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₆cycloalkyl, C₆₋₁₄ aryl, and C₇₋₁₆ aralkyl group,        -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,            C₃₋₆cycloalkyl, C₆₋₁₄ aryl, or C₇₋₁₆ aralkyl is optionally            substituted with one or more substituents selected from a            Substituent Group A,    -   (iii) —(C═O)—R⁵, —(C═O)—OR⁵, —(C═O)—NR⁵R⁶, —(C═S)—NHR⁵, or        —SO²—R⁷,    -   wherein:        -   R⁵ hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆            cycloalkyl, C₆₋₁₄ aryl, or C₇₋₁₆ aralkyl,            -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆                cycloalkyl, C₆₋₁₄ aryl, or C₇₋₁₆ aralkyl is optionally                substituted with one or more substituents selected from                the Substituent Group A,        -   R⁶ is hydrogen or C₁₋₆ alkyl,        -   R⁷ is C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆            cycloalkyl, a C₆₋₁₄ aryl, or C₇₋₁₆ aralkyl,            -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆                cycloalkyl, C₆₋₁₄ aryl, or C₇₋₁₆ aralkyl is optionally                substituted with one or more substituents selected from                the Substituent Group A, or    -   (iv) an amino group optionally substituted with substituents        selected from:        -   (a) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,            C₆₋₁₄ aryl, or C₇₋₁₆ aralkyl,            -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆                cycloalkyl, C₆₋₁₄ aryl, and a        -   C₇₋₁₆ aralkyl is optionally substituted with one or more            substituents selected from the Substituent Group A,        -   (b) —(C═O)—R⁵, —(C═O)—OR⁵, —(C═O)—NR⁵R⁶, —(C═S)—NHR⁵, or            —SO²—R⁷, and        -   (c) C₁₋₆ alkylidene optionally substituted with one or more            substituents selected from the Substituent Group A-   R² is a C₆₋₁₄ monocyclic or fused polycyclic aryl optionally    substituted with one or more substituents selected from the    Substituent Group A;-   R³ is hydrogen or C₆₋₁₄ aryl, wherein the C₆₋₁₄ aryl is optionally    substituted with one more substituents selected from the Substituent    Group A;-   X is —S—, —S(O)—, or —S(O)₂—;-   Y is a bond, —O—, —S—, —S(O)—, —S(O)₂—, or NR⁴,    -   wherein R⁴ is:        -   (a) hydrogen,        -   (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,            C₆₋₁₄ aryl, or C₇₋₁₆ aralkyl,            -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆                cycloalkyl, C₆₋₁₄ aryl, and C₇₋₁₆ aralkyl is optionally                substituted with one or more substituents selected from                the Substituent Group A, or        -   (c) —(C═O)—R⁵, —(C═O)—OR⁵, —(C═O)—NR⁵R⁶, —(C═S)—NHR⁵, or            —SO²—R⁷;-   Z is a bond, C₁₋₁₅ alkylene, C₂₋₁₆ alkenylene, or C₂₋₁₆ alkynylene,    -   wherein the C₁₋₁₅ alkylene, C₂₋₁₆ alkenylene, or C₂₋₁₆        alkynylene is optionally substituted with one or more        substituents selected from the Substituent Group A; and-   a substituent of the Substituent Group A is selected from: oxo,    halogen, C₁₋₃ alkylenedioxy, nitro, cyano, optionally halogenated    C₁₋₆ alkyl, optionally halogenated C₂₋₆ alkenyl, carboxy C₂₋₆    alkenyl, optionally halogenated C₂₋₆ alkynyl, optionally halogenated    C₃₋₆ cycloalkyl, C₆₋₁₄ aryl, optionally halogenated C₁₋₈ alkoxy,    C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkoxy, hydroxy, C₆₋₁₄ aryloxy, C₇₋₁₆    aralkyloxy, mercapto, optionally halogenated C₁₋₆ alkylthio, C₆₋₁₄    arylthio, C₇₋₁₆ aralkylthio, amino, mono-C₁₋₆ alkylamino, mono-C₆₋₁₄    arylamino, di-C₁₋₆alkylamino, di-C₆₋₁₄ arylamino, formyl, carboxy,    C₁₋₆ alkyl-carbonyl, C₃₋₆cycloalkyl-carbonyl, C₁₋₆ alkoxy-carbonyl,    C₆₋₁₄ aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄ aryloxy-carbonyl,    C₇₋₁₆ aralkyloxy-carbonyl, carbamoyl, thiocarbamoyl, mono-C₁₋₆    alkyl-carbamoyl, di-C₁₋₆ alkyl-carbamoyl, C₆₋₁₄aryl-carbamoyl, C₁₋₆    alkylsulfonyl, C₆₋₁₄ arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄    arylsulfinyl, formylamino, C₁₋₆ alkyl-carbonylamino, C₆₋₁₄    aryl-carbonylamino, C₁₋₆ alkoxy-carbonylamino, C₁₋₆    alkylsulfonylamino, C₆₋₁₄ arylsulfonylamino, C₁₋₆ alkyl-carbonyloxy,    C₆₋₁₄ aryl-carbonyloxy, C₁₋₆ alkoxy-carbonyloxy, mono-C₁₋₆    alkyl-carbamoyloxy, di-C₁₋₆ alkyl-carbamoyloxy, C₆₋₁₄    aryl-carbamoyloxy, sulfo, sulfamoyl, sulfinamoyl and sulfenamoyl.

In some embodiments, the p38 kinase inhibitor from Genus I is selectedfrom the following:

-   (F)    N-[5-[2-benzoylamino-4-pyridyl)-4-(3,5-dimethylphenyl)-1,3-thiazol-2-yl]acetamide;-   N-[5-(2-benzylamino-4-pyridyl)-4-(3,5-dimethylphenyl)-1,3-thiazol-2-yl]acetamide;-   N-[4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide;-   N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide;-   N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide;-   N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide;-   N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide;-   N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide;-   N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide;-   N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide;-   N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-(4-methoxyphenyl)propionamide;-   N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-4-phenylbutyramide;-   N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide;-   N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide;-   N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide;-   N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide;-   N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide;-   N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide;-   N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide;-   N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide;-   N-benzyl-N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine;-   N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine;-   N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine;-   N-benzyl-N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]amine;-   N-[4-(4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine;-   N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine;-   N-benzyl-N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine;-   N-(4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine;-   N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine;-   N-benzyl-N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine;-   N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine-   N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine;-   N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide-   N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide-   N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide-   N-benzyl-N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine;-   N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine;-   N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine;-   N-(4-fluorobenzyl)-N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine;-   (E)    [4-(3,5-dimethylphenyl)-5-(2-phenylmethyloxy-4-pyridyl)-1,3-thiazol-2-yl]amine;-   N-[4-[2-benzoylamino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide;-   N-[4-(4-methoxyphenyl)-5-[2-[(3-pyridylcarbonylamino)]-4-pyridyl]-1,3-thiazol-2-yl]nicotinamide;-   N-[4-[2-amino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide;-   N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide;-   N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzylamine;-   N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide;    hydrochloride;-   N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzylamine    dihydrochloride; and-   N-(4-(2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide    (“TAK-715”), Formula (I′).

In one embodiment, the p38 kinase inhibitor isN-(4-(2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylThenzamide(“TAK-715”), Formula (I′).

Genus I Definitions

In the aforementioned Formula, R¹ represents a hydrogen atom, ahydrocarbon group optionally having substituents, a heterocyclic groupoptionally having substituents, an amino group optionally havingsubstituents or acyl group.

As “acyl group” represented by R¹, for example, there are an acyl grouprepresented by the Formula: —(C═O)—R⁵, —(C═O)—OR⁵, —(C═O)—NR⁵R⁶,—(C═S)—NHR⁵ or —SO₂—R⁷ (wherein R⁵ represents a hydrogen atom, ahydrocarbon group optionally having substituents or a heterocyclic groupoptionally having substituents, R⁶ represents a hydrogen atom or aC₁₋₆alkyl, R⁷ represents a hydrocarbon group optionally havingsubstituents or a heterocyclic group optionally having substituents) andthe like.

In the aforementioned Formula, as “hydrocarbon group” of “hydrocarbongroup optionally having substituents”, for example, there are an acyclicor cyclic hydrocarbon group (for example, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, aralkyl and the like) and the like. Among them,acyclic or cyclic hydrocarbon groups having carbon number of 1 to 16 arepreferable.

As “alkyl”, for example, C₁₋₆ alkyl (for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and thelike) is preferable and, in particular, C₁₋₃ alkyl (for example, methyl,ethyl, propyl and isopropyl) and the like are preferable.

As “alkenyl”, for example, C₂₋₆ alkenyl (for example, vinyl, allyl,isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl,1-methyl-2-propenyl, 2-methyl-1-propenyl and the like) and the like arepreferable.

As “alkynyl”, for example, C₂₋₆ alkynyl (for example, ethynyl,propargyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-hexynyl and the like) andthe like are preferable.

As “cycloalkyl”, for example, C₃₋₆ cycloalkyl (for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and the like) and the like arepreferable.

As “aryl”, for example, C₆₋₁₄ aryl (for example, phenyl, 1-naphthyl,2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and thelike) and the like are preferable.

As “aralkyl”, for example, C₇₋₁₆ aralkyl (for example, benzyl,phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl,2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl and thelike) and the like are preferable.

As “substituents” of “hydrocarbon group optionally having substituents”represented by R⁵, for example, there are oxo, halogen atom (forexample, fluorine, chlorine, bromine, iodine and the like), C₁₋₃alkylenedioxy (for example, methylenedioxy, ethylenedioxy and the like),nitro, cyano, optionally halogenated C₁₋₆ alkyl, optionally halogenatedC₂₋₆ alkenyl, carboxy C₂₋₆ alkenyl (for example, 2-carboxyethenyl,2-carboxy-2-methylethenyl and the like), optionally halogenated C₂₋₆alkynyl, optionally halogenated C₃₋₆ cycloalkyl, C₆₋₁₄ aryl (forexample, phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl,4-biphenylyl, 2-anthryl and the like), optionally halogenated C₁₋₈alkoxy, C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkoxy (for example,ethoxycarbonylmethyloxy and the like), hydroxy, C₆₋₁₄ aryloxy (forexample, phenyloxy, 1-naphthyloxy, 2-naphthyloxy and the like),C₇₋₁₆aralkyloxy (for example, benzyloxy, phenethyloxy and the like),mercapto, optionally halogenated C₁₋₆ alkylthio, C₆₋₁₄ arylthio (forexample, phenylthio, 1-naphthylthio, 2-naphthylthio and the like), C₇₋₁₆aralkylthio (for example, benzylthio, phenethylthio and the like),amino, mono-C₁₋₆alkylamino (for example, methylamino, ethylamino and thelike), mono-C₆₋₁₄ arylamino (for example, phenylamino, 1-naphthylamino,2-naphthylamino and the like), di-C₁₋₆ alkylamino (for example,dimethylamino, diethylamino, ethylmethylamino and the like),di-C₆₋₁₄arylamino (for example, diphenylamino and the like), formyl,carboxy, C₁₋₆alkyl-carbonyl (for example, acetyl, propionyl and thelike), C₃₋₆ cycloalkyl-carbonyl (for example, cyclopropylcarbonyl,cyclopentylcarbonyl, cyclohexylcarbonyl and the like), C₁₋₆alkoxy-carbonyl (for example, methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, tert-butoxycarbonyl and the like), C₆₋₁₄ aryl-carbonyl(for example, benzoyl, 1-naphthoyl, 2-naphthoyl and the like), C₇₋₁₆aralkyl-carbonyl (for example, phenylacetyl, 3-phenylpropionyl and thelike), C₆₋₁₄ aryloxy-carbonyl (for example, phenoxycarbonyl and thelike), C₇₋₁₆ aralkyloxy-carbonyl (for example, benzyloxycarbonyl,phenethyloxycarbonyl and the like), 5 or 6 membered heterocycliccarbonyl (for example, nicotinoyl, isonicotinoyl, thenoyl, furoyl,morpholinocarbonyl, thiomorpholinocarbonyl, piperazin-1-ylcarbonyl,pyrrolidin-1-ylcarbonyl and the like), carbamoyl, thiocarbamoyl,mono-C₁₋₆alkyl-carbamoyl (for example, methylcarbamoyl, ethylcarbamoyland the like), di-C₁₋₆ alkyl-carbamoyl (for example, dimethylcarbamoyl,diethylcarbamoyl, ethylmethylcarbamoyl and the like), C₆₋₁₄aryl-carbamoyl (for example, phenylcarbamoyl, 1-naphthylcarbamoyl,2-naphthylcarbamoyl and the like), 5 or 6 membered heterocycliccarbamoyl (for example, 2-pyridylcarbamoyl, 3-pyridylcarbamoyl,4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl and thelike), C₁₋₆ alkylsulfonyl (for example, methylsulfonyl, ethylsulfonyland the like), C₆₋₁₄ arylsulfonyl (for example, phenylsulfonyl,1-naphthylsulfonyl, 2-naphthylsolfonyl and the like), C₁₋₆ alkylsulfinyl(for example, methylsulfinyl, ethylsulfinyl and the like), C₆₋₁₄arylsulfinyl (for example, phenylsulfinyl, 1-naphthylsulfinyl,2-naphthylsulfinyl and the like), formylamino, C₁₋₆ alkyl-carbonylamino(for example, acetylamino and the like), C₆₋₁₄ aryl-carbonylamino (forexample, benzoylamino, naphthoylamino and the like), C₁₋₆alkoxy-carbonylamino (for example, methoxycarbonylamino,ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino and thelike), C₁₋₆alkylsulfonylamino (for example, methylsulfonylamino,ethylsulfonylamino and the like), C₆₋₁₄ arylsulfonylamino (for example,phenylsulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonylaminoand the like), C₁₋₆ alkyl-carbonyloxy (for example, acetoxy,propionyloxy and the like), C₆₋₁₄ aryl-carbonyloxy (for example,benzoyloxy, naphthylcarbonyloxy and the like), C₁₋₆ alkoxy-carbonyloxy(for example, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy,butoxycarbonyloxy and the like), mono-C₁₋₆ alkyl-carbamoyloxy (forexample, methylcarbamoyloxy, ethylcarbamoyloxy and the like), di-C₁₋₆alkyl-carbamoyloxy (for example, dimethylcarbamoyloxy,diethylcarbamoyloxy and the like), C₆₋₁₄ aryl-carbamoyloxy (for example,phenylcarbamoyloxy, naphthylcarbamoyloxy and the like), nicotinoyloxy, 5to 7 membered saturated cyclic amino optionally having substituents, 5to 10 membered aromatic heterocyclic group (for example, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl,4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl,4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl,2-benzothiazolyl, 2-benzo [b]thienyl, 3-benzo[b]thienyl,2-benzo[b]furanyl, 3-benzo[b]furanyl and the like), sulfo, sulfamoyl,sulfinamoyl, sulfenamoyl and the like.

The “hydrocarbon group” may have 1 to 5, preferably 1 to 3aforementioned substituents at a substitutable position and, when thenumber of substituents is 2 or more, respective substituents may be thesame or different.

As aforementioned “optionally halogenated C₁₋₆ alkyl”, for example,there are C₁₋₆ alkyl (for example, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like) andthe like optionally having 1 to 5, preferably 1 to 3 halogen atoms (forexample, fluorine, chlorine, bromine, iodine and the like). Examplesthereof are methyl, chloromethyl, difluoromethyl, trichloromethyl,trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl,pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl,4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyland the like.

As the aforementioned “optionally halogenated C₂₋₆ alkenyl”, forexample, there are C₂₋₆ alkenyl (for example, vinyl, propenyl,isopropenyl, 2-buten-1-yl, 4-penten-1-yl, 5-hexen-1-yl) and the likeoptionally having 1 to 5, preferably 1 to 3 halogen atoms (for example,fluorine, chlorine, bromine, iodine and the like).

As the aforementioned “optionally halogenated C₂₋₆ alkynyl”, there areC₂₋₆alkynyl (for example, 2-butyn-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yl andthe like) and the like optionally having 1 to 5, preferably 1 to 3halogen atoms (for example, fluorine, chlorine, bromine, iodine and thelike).

As the aforementioned “optionally halogenated C₃₋₆ cycloalkyl”, forexample, there are C₃₋₆ cycloalkyl (for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and the like) and the likeoptionally having 1 to 5, preferably 1 to 3 halogen atoms (for example,fluorine, chlorine, bromine, iodine and the like). Examples thereof arecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl,4-chlorocyclohexyl and the like.

As the aforementioned “optionally halogenated C₁₋₈alkoxyl”, for example,there are C₁₋₈ alkoxy (for example, methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and thelike) and the like optionally having 1 to 5, preferably 1 to 3 halogenatoms (for example, fluorine, chlorine, bromine, iodine and the like).Examples thereof are methoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy andthe like.

As the aforementioned “optionally halogenated C₁₋₆ alkylthio”, forexample, there are C₁₋₆ alkylthio (for example, methylthio, ethylthio,propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio andthe like) and the like optionally having 1 to 5, preferably 1 to 3halogen atoms (for example, fluorine, chlorine, bromine, iodine and thelike). Examples thereof are methylthio, difluoromethylthio,trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio,4,4,4-trifluorobutylthio, pentylthio, hexylthio and the like.

As “5 to 7 membered saturated cyclic amino” of the aforementioned “5 to7 membered saturated cyclic amino optionally having substituents”, thereare 5 to 7 membered saturated cyclic amino optionally containing 1 to 4heteroatoms of one or two kinds selected from a nitrogen atom, a sulfuratom and an oxygen atom in addition to one nitrogen atom and carbonatoms and examples thereof are pyrolidin-1-yl, piperidino,piperazin-1-yl, morpholino, thiomorpholino, hexahydroazepin-1-yl and thelike.

As “substituents” of the “5 to 7 membered saturated cyclic aminooptionally having substituents”, for example, there are 1 to 3 C₁₋₆alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl and the like), C₆₋₁₄ aryl (forexample, phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl,4-biphenylyl, 2-anthryl and the like), C₁₋₆ alkyl-carbonyl (for example,acetyl, propionyl and the like), 5 to 10 membered aromatic heterocyclicgroup (for example, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl,1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl,2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl,3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl and the like),oxo and the like.

As “heterocyclic group” of “heterocyclic group optionally havingsubstituents” represented by R⁵, for example, there is a monovalentgroup obtained by removing one arbitrary hydrogen atom from a 5 to 14membered (monocyclic, bicyclic or tricyclic) heterocycle containing 1 to4 heteroatoms of one or two kinds selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms, preferably(i) a 5 to 14 membered (preferably 5 to 10 membered, particularlypreferably 5 to 6 membered) aromatic heterocycle, (ii) a 5 to 10membered (preferably 5 to 6 membered) non-aromatic heterocycle or (iii)a 7 to 10 membered bridged heterocycle.

As the aforementioned “5 to 14 membered (preferably 5 to 10 membered)aromatic heterocycle”, there are an aromatic heterocycle such asthiophene, benzo[b]thiophene, benzo[b]furan, benzimidazole, benzoxazole,benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, pyrrole,imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole,isoindole, 1H-indazole, purine, 4H-quinolizine, isoquinoline, quinoline,phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,carbazole, β-carboline, phenanthridine, acridine, phenazine, thiazole,isothiazole, phenothiazine, isoxazole, furazan, phenoxazine and thelike, and a ring formed by fusing these rings (preferably monocyclic)with 1 or a plurality (preferably 1 to 2) of aromatic rings (forexample, benzene ring and the like).

As the aforementioned “5 to 10 membered non-aromatic heterocycle”, forexample, there are pyrrolidine, imidazoline, pyrazolidine, pyrazoline,piperidine, piperazine, morpholine, thiomorpholine, dioxazole,oxadiazoline, thiadiazoline, triazoline, thiadiazole, dithiazole and thelike.

As the aforementioned “7 to 10 membered bridged heterocycle”, forexample, there are quinuclidine, 7-azabicyclo[2.2.1]heptane and thelike.

The “heterocyclic group” is preferably a 5 to 14 membered (preferably 5to 10 membered) (monocyclic or bicyclic) heterocyclic group containingpreferably 1 to 4 heteroatoms of one or two kinds selected from anitrogen atom, a sulfur atom and an oxygen atom in addition to carbonatoms. More particularly, examples thereof are an aromatic heterocyclicgroup such as 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl,8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl,pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl,3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-indolyl, 2-indolyl,3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl,2-benzo[b]furanyl, 3-benzo[b]furanyl and the like, and a non-aromaticheterocyclic group such as 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-imidazolinyl, 4-imidazolinyl, 2-pyrazolidinyl,3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl,4-piperidyl, 1-piperazinyl, 2-piperazinyl, morpholino, thiomorpholinoand the like.

Among them, for example, a 5 or 6 membered heterocyclic group containing1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and anoxygen atom in addition to carbon atoms is further preferable. Moreparticularly, examples thereof are 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, pyrazinyl, 2-pyrimidinyl,3-pyrrolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-pyrrolidinyl,2-pyrrolidinyl, 3-pyrrolidinyl, 2-imidazolinyl, 4-imidazolinyl,2-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino,2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl,morpholino, thiomorpholino and the like.

As “substituents” of “heterocyclic group optionally havingsubstituents”, for example, there are the same “substituents” assubstituents of “hydrocarbon group optionally having substituents”represented by R⁵.

The “heterocyclic group” may have 1 to 5, preferably 1 to 3aforementioned substituents at a substitutable position and, when thenumber of substituents is 2 or more, respective substituents may be thesame or different.

As “C₁₋₆ alkyl” represented by R⁶, for example, there are methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyland the like.

As “hydrocarbon group optionally having substituents” and “heterocyclicgroup optionally having substituents” represented by R⁷, for example,there are the aforementioned “hydrocarbon group optionally havingsubstituents” and “heterocyclic group optionally having substituents”represented by R⁵, respectively.

As “hydrocarbon group optionally having substituents” and “heterocyclicgroup optionally having substituents” represented by R¹, for example,there are the aforementioned “hydrocarbon group optionally havingsubstituents” and “heterocyclic group optionally having substituents”represented by R⁵, respectively.

As “amino group optionally having substituents” represented by R¹, forexample, there are (1) an amino group optionally having 1 or 2substituents and (2) a cyclic amino group optionally having substituentsand the like.

As “substituents” of “amino group optionally having 1 or 2 substituents”of the aforementioned (1), for example, there are a hydrocarbon groupoptionally having substituents, a heterocyclic group optionally havingsubstituents, an acyl group, an alkylidene group optionally havingsubstituents and the like. As these “hydrocarbon group optionally havingsubstituents” and “heterocyclic group optionally having substituents”,there are the same “hydrocarbon group optionally having substituents”and “heterocyclic group optionally having substituents” as thoserepresented by R⁵ described above, respectively. As the “acyl group”,there is the same “acyl group” as that by represented by R¹ as describedabove.

As “alkylidene group” of “alkylidene group optionally havingsubstituents”, for example, there are a C₁₋₆ alkylidene group (forexample, methylidene, ethylidene, propylidene and the like) and thelike. As “substituents” of “alkylidene group optionally havingsubstituents”, there are 1 to 5, preferably 1 to 3 same substituents as“substituents” of “hydrocarbon group optionally having substituents”represented by R⁵.

When the number of the aforementioned “substituents” of “amino groupoptionally having 1 or 2 substituents” is 2, respective substituents maybe the same or different.

As “cyclic amino group” of “cyclic amino group optionally havingsubstituents” of the aforementioned (2), there are a 5 to 7 memberednon-aromatic cyclic amino group optionally containing 1 to 4 heteroatomsof one or two kinds selected from a nitrogen atom, a sulfur atom and anoxygen atom in addition to one nitrogen atom and carbon atoms. Moreparticularly, examples thereof are pyrrolidin-1-yl, piperidino,piperazin-1-yl, morpholino, thiomorpholino, hexahydroazepin-1-yl,imidazolidin-1-yl, 2,3-dihydro-1H-imidazol-1-yl,tetrahydro-1(2H)-pyrimidinyl, 3,6-dihydro-1(2H)-pyrimidinyl,3,4-dihydro-1(2H)-pyrimidinyl and the like. As “substituents” of “cyclicamino optionally having substituents”, there are 1 to 3 same ones as“substituents” of “5 to 7 membered saturated cyclic amino group” whichwere described in detail as “substituents” of “hydrocarbon groupoptionally having substituents” represented by R⁵.

Examples of the 5 to 7 membered non-aromatic cyclic amino group having 1oxo, there are 2-oxoimidazolidin-1-yl,2-oxo-2,3-dihydro-1H-imidazol-1-yl, 2-oxotetrahydro-1(2H)-pyrimidinyl,2-oxo-3,6-dihydro-1(2H)-pyrimidinyl,2-oxo-3,4-dihydro-1(2H)-pyrimidinyl, 2-oxopyrrolidin-1-yl,2-oxopiperidino, 2-oxopiperazin-1-yl, 3-oxopiperazin-1-yl,2-oxo-2,3,4,5,6,7-hexahydroazepin-1-yl and the like.

As R¹, an amino group optionally having substituents, an aryl groupoptionally having substituents and an alkyl group optionally havingsubstituents and the like are preferable.

As further preferable example of the “amino group optionally havingsubstituents” is an amino group optionally having 1 or 2 acylrepresented by the Formula: —(C═O)—R⁵, —(C═O)—OR⁵, —(C═O)—NR⁵R⁶,—(C═S)—NHR⁵ or —SO₂—R⁷ [wherein respective symbols represent the samemeanings as described above]. Particularly preferable example is anamino group optionally having 1 or 2 acyl represented by the Formula:—C(C═O)—R⁵ or —(C═O)—NR⁵R⁶ [wherein respective symbols represent thesame meanings as described above].

As the “aryl group optionally having substituents”, for example, thereis preferably a C₆₋₁₄ aryl group (preferably a phenyl group and thelike) optionally having 1 to 5 substituents selected from C₁₋₆alkylthio, C₆₋₁₄arylthio, C₁₋₆ alkylsulfinyl, C₆₋₁₄ arylsulfinyl, C₁₋₆alkylsulfonyl, C₆₋₁₄arylsulfonyl and carboxy.

As the “alkyl group optionally having substituents”, for example, aC₁₋₆alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl and the like) optionally substitutedwith 1 to 3 substituents selected from halogen atom, C₁₋₆ alkoxy,hydroxy, carboxy and C₁₋₆ alkoxy-carbonyl and the like are preferable,and particularly C₁₋₃alkyl group such as methyl, ethyl and the like ispreferable.

Among them, as R¹, (i) C₁₋₆ alkyl group (for example, C₁₋₄ alkyl groupsuch as methyl, ethyl, propyl, butyl), (ii) a C₆₋₁₄ aryl group (forexample, a phenyl group) optionally substituted with substituentsselected from C₁₋₆ alkylthio (for example, methylthio), C₁₋₆alkylsulfonyl (for example, methylsulfonyl) and halogen atom (forexample, chlorine atom, fluorine atom) or (iii) an amino groupoptionally having 1 or 2 acyl represented by the Formula: —(C═O)—R⁵′(wherein R⁵′ represents {circle around (1)} a C₁₋₆ alkyl group (forexample, C₁₋₃ alkyl group such as methyl), {circle around (2)} aC₆₋₁₄aryl group (for example, a phenyl group) or {circle around (3)} a 5to 14 membered heterocyclic group containing 1 to 4 heteroatoms of oneor two kinds selected from a nitrogen atom, a sulfur atom and an oxygenatom in addition to carbon atoms (for example, a 5 to 6 memberedheterocyclic group containing 1 to 2 heteroatoms selected from anitrogen atom, a sulfur atom and an oxygen atom in addition to carbonatoms such as pyridyl group) are preferable. As R⁵′ and R⁵″, a phenylgroup or a pyridyl group is suitable.

In the aforementioned Formula, R2 represents an aromatic groupoptionally having substituents.

As “aromatic group” of “aromatic group optionally having substituents”represented by R², for example, there are an aromatic hydrocarbon group,an aromatic heterocyclic group and the like.

As the “aromatic hydrocarbon group”, examples thereof include aC₆₋₁₄monocyclic or fused polycyclic (bicyclic or tricyclic) aromatichydrocarbon group, etc. As examples, there are a C₆₋₁₄ aryl group andthe like such as phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl,3-biphenylyl, 4-biphenylyl, 2-anthryl and the like and, furtherpreferably, a C₆₋₁₀ aryl group and the like (for example, phenyl,1-naphthyl, 2-naphthyl and the like, preferably phenyl and the like).

As the “aromatic heterocyclic group”, there is a monovalent groupobtained by removing one arbitrary hydrogen atom from 5 to 14 membered(preferably 5 to 10 membered) aromatic heterocycle containing 1 to 4heteroatoms of one or two kinds selected from nitrogen atom, sulfur atomand oxygen atom in addition to carbon atoms.

As the aforementioned “5 to 14 membered (preferably 5 to 10 membered)aromatic heterocycle”, for example, there are an aromatic heterocyclesuch as thiophene, benzo[b]thiophene, benzo[b]furan, benzimidazole,benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene,furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine,pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolizine,isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline,quinazoline, cinnoline, carbazole, β-carboline, phenanthridine,acridine, phenazine, thiazole, isothiazole, phenothiazine, isoxazole,furazan, phenoxazine and the like, and a ring formed by fusing theserings (preferably monocycle) with 1 or a plurality of (preferably 1 or2) aromatic rings (for example, benzene ring and the like).

As the “aromatic heterocyclic group”, there are preferably a 5 to 14membered (preferably 5 to 10 membered)(monocyclic or bicyclic) aromaticheterocyclic group containing preferably 1 to 4 heteroatoms of one ortwo kinds selected from a nitrogen atom, a sulfur atom and an oxygenatom in addition to carbon atoms and the like and, more particularly,there are an aromatic heterocyclic group such as 2-thienyl, 3-thienyl,2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl,3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl,3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, pyrazinyl, 2-pyrimidinyl,4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl,3-isoxazolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl,2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl,3-benzo[b]furanyl and the like.

As “substituents” of “aromatic group optionally having substituents”,there are 1 to 5, preferably 1 to 3 same substituents as “substituents”of “hydrocarbon group optionally having substituents” represented by R⁵.When the number of substituents is 2 or more, respective substituentsmay be the same or different.

As R², (1) a C₆₋₁₄ aryl group optionally having substituents and (2) a 5to 14 membered aromatic heterocyclic group containing 1 to 4 heteroatomsof one or two kinds selected from a nitrogen atom, a sulfur atom and anoxygen atom in addition to carbon atoms are preferable and, among them,(1) a C₆₋₁₄ aryl group (for example, phenyl group, naphthyl group)optionally substituted with halogen atom (for example, chlorine atom,fluorine atom) or C₁₋₆ alkoxy (for example, methoxy), (2) a 5 to 14membered aromatic heterocyclic group containing 1 to 4 heteroatoms ofone or two kinds selected from a nitrogen atom, a sulfur atom and anoxygen atom in addition to carbon atoms (for example, a 5 to 6 memberedaromatic heterocyclic group containing 1 to 2 heteroatoms selected froma nitrogen atom, a sulfur atom and an oxygen atom in addition to carbonatoms such as pyridyl group, thienyl group) and the like are preferableand, in particular, a phenyl group, a pyridyl group and the like aresuitable.

In the aforementioned Formula, R³ represents a hydrogen atom, a pyridylgroup optionally having substituents or an aromatic hydrocarbon groupoptionally having substituents.

As “substituents” of “pyridyl group optionally having substituents”represented by R³, there are the same substituents as “substituents” of“hydrocarbon group optionally having substituents” represented by R⁵.

The “pyridyl group” may, for example, have 1 to 5, preferably 1 to 3aforementioned substituents at substitutable positions and, when thenumber of substituents is 2 or more, respective substituents may be thesame or different. In addition, an intracyclic nitrogen atom may beN-oxidized.

As “aromatic hydrocarbon group” of “aromatic hydrocarbon groupoptionally having substituents” represented by R³, there is the samearomatic hydrocarbon group as “aromatic hydrocarbon group” of “aromatichydrocarbon group optionally having substituents” represented by R² and,preferably, there are a C₆₋₁₄ aryl group and the like such as phenyl,1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl,2-anthryl and the like and, further preferably, a C₆₋₁₀ aryl group andthe like (for example, phenyl, 1-naphthyl, 2-naphthyl and the like,preferably phenyl and the like) and the like. As “substituents” of“aromatic hydrocarbon group optionally having substituents” representedby R³, there are the same substituents as substituents of “aromaticgroup optionally having substituents” represented by R².

As R³, a C₆₋₁₄ aryl group optionally having substituents is preferableand, among them, a C₆₋₁₄ aryl group optionally substituted with 1 or 2C₁₋₆ alkyl (for example, methyl, ethyl and the like) or C₁₋₆ alkoxy (forexample, methoxy, ethoxy and the like) is preferable and, in particular,a phenyl group optionally substituted with 1 or 2 C₁₋₆ alkyl or C₁₋₆alkoxy (for example, 3-methoxyphenyl, 2-methylphenyl, 2,4-dimethylphenyland the like) is suitable.

In the aforementioned Formula, X represents an oxygen atom or anoptionally oxidized sulfur atom.

As “optionally oxidized sulfur atom” represented by X, there are S, SOand SO₂.

As X, there is preferably an optionally oxidized sulfur atom. Furtherpreferably, it is S.

In the aforementioned Formula, Y represents a bond, an oxygen atom, anoptionally oxidized sulfur atom or the Formula NR⁴ (wherein R⁴represents a hydrogen atom, a hydrocarbon group optionally havingsubstituents or an acyl group).

As “optionally oxidized sulfur atom” represented by Y, there are S, SOand SO2.

As “hydrocarbon group optionally having substituents” represented by R4,for example, there is the same group as “hydrocarbon group optionallyhaving substituents” represented by R⁵. Among them, a C₁₋₆ alkyl groupsuch as methyl, ethyl and the like and, in particular, a C₁₋₃ alkylgroup such as methyl and the like is preferable.

As “acyl group” represented by R⁴, there is the same group as “acylgroup” represented by R¹.

As Y, an oxygen atom, an optionally oxidized sulfur atom, a grouprepresented by the Formula NR⁴ (wherein R⁴ represents the same meaningas that described above) and the like are preferable and, among them, anoxygen atom, an optionally oxidized sulfur atom, a group represented bythe Formula NR⁴′ (R⁴′ represents a hydrogen group or a C₁₋₆ alkyl group)and the like are preferable and, further, an oxygen atom, S, SO₂, NH,N(CH₃) and the like are preferable and, in particular, O or NH issuitable.

In the aforementioned Formula, Z represents a bond or a divalent acyclichydrocarbon group optionally having substituents.

As “divalent acyclic hydrocarbon group” of “divalent acyclic hydrocarbongroup optionally having substituents”, for example, there are aC₁₋₁₅alkylene group (for example, methylene, ethylene, propylene,butylene, pentamethylene, hexamethylene, heptamethylene, octamethyleneand the like, preferably a C₁₋₆ alkylene group and the like), a C₂₋₁₆alkenylene group (for example, vinylene, propylene, 1-butenylene,2-butenylene, 1-pentenylene, 2-pentenylene, 3-pentenylene and the like),a C₂₋₁₆ alkynylene group (ethynylene, propynylene, 1-butynylene,2-butynylene, 1-pentynylene, 2-pentynylene, 3-pentynylene and the like)and the like, preferably, a C₁₋₁₅alkylene group, particularlypreferably, a C₁₋₆ alkylene group and the like. As “substituents” of“divalent acyclic hydrocarbon group optionally having substituents”represented by Z, for example, there are the same substituents as“substituents” of “hydrocarbon group optionally having substituents”represented by R⁵.

As Z, a lower alkylene group optionally having C₁₋₃ alkyl (for example,methyl), oxo and the like (for example, a C₁₋₆ alkylene group such asmethylene, ethylene, propylene and the like, in particular, a C₁₋₃alkylene group) is preferable and, among them, a C₁₋₆ alkylene groupoptionally having oxo (for example, a C₁₋₃ alkylene group such asmethylene, ethylene, propylene, in particular, methylene) is suitable.

More particularly, as Z, —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —CO—, —CH₂CO—,—(CH₂)₂CO—, —CH(CH₃)— and the like are used and, in particular, —CH₂—,—CO— and the like are suitable.

A nitrogen atom in Formula (I) may be N-oxidized. For example, anitrogen atom which is a constituent atom of 4-pyridyl group as asubstituent at 5-position of a ring represented by the Formula:

wherein a symbol in the Formula represents the same meaning as thatdescribed above, may be N-oxidized. As Formula (I), for example, acompound represented by the Formula:

wherein n represents 0 or 1, and other symbols represents the samemeanings as those described above, or salts thereof are preferable.

As Formula (I), compounds shown by the following (A) to (F) arepreferably used.

(A) Formula (I) wherein R¹ is an amino group optionally havingsubstituents, R² is a C₆₋₁₄ aryl group optionally having substituents,R³ is a C₆₋₁₄ aryl group optionally having substituents, X is a sulfuratom, Y is an oxygen atom or a group represented by the Formula NR⁴(wherein R⁴ represents the same meaning as that described above) or(and) Z is a lower alkylene group optionally having substituents.

(B) Formula (I) wherein R¹ is (i) a C₁₋₆ alkyl group (for example, aC₁₋₄alkyl group such as methyl, ethyl, propyl, butyl and the like),

(ii) a C₆₋₁₄ aryl group (for example, a phenyl group) optionallysubstituted with substituents selected from C₁₋₆ alkylthio (for example,methylthio), C₁₋₆ alkylsulfonyl (for example, methylsulfonyl) andhalogen atom (for example, chlorine atom, fluorine atom), or

(iii) an amino group optionally having 1 or 2 acyl represented by theFormula: —(C═O)—R⁵′ [wherein R⁵′ represents {circle around (1)} aC₁₋₆alkyl group (for example, C₁₋₃ alkyl group such as methyl and thelike), {circle around (2)} a C₆₋₁₄ aryl group (for example, a phenylgroup) or {circle around (3)} a 5 to 14 membered heterocyclic groupcontaining 1 to 4 heteroatoms of one or two kinds selected from anitrogen atom, a sulfur atom and an oxygen atom in addition to carbonatoms (for example, a 5 to 6 membered heterocyclic group containing 1 to2 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygenatom in addition to carbon atoms such as a pyridyl group);

R² is a C₆₋₁₄ aryl group (for example, a phenyl group, a naphthyl group)optionally substituents with halogen atom (for example, chlorine atom,fluorine atom) or C₁₋₆ alkoxy (for example, methoxy), or a 5 to 14membered aromatic heterocyclic group containing 1 to 4 heteroatoms ofone or two kinds selected from a nitrogen atom, a sulfur atom and anoxygen atom in addition to carbon atoms (for example, a 5 to 6 memberedaromatic heterocyclic group containing 1 to 2 heteroatoms selected froma nitrogen atom, a sulfur atom and an oxygen atom in addition to carbonatoms such as a pyridyl group, a thienyl group and the like);

R³ is a C₆₋₁₄ aryl group (particularly, a phenyl group) optionallysubstituted with 1 or 2 C₁₋₆ alkyl (for example, methyl) or C₁₋₆ alkoxy(for example, methoxy);

X is a sulfur atom;

Y is an oxygen atom, an optionally oxidized sulfur atom or a grouprepresented by the Formula NR⁴′ (R⁴′ is a hydrogen atom or a C₁₋₆ alkylgroup) (in particular, an oxygen atom, S, SO₂, NH, N(CH₃) and the like);

Z is a C₁₋₆ alkylene group (in particular, a C₁₋₃ alkylene group)optionally having oxo or C₁₋₆ alkyl (for example, C₁₋₃ alkyl such asmethyl) or a bond.

(C) Formula (I) wherein R1 is an amino group optionally having 1 or 2acyl represented by the Formula —(C═O)—R5″ (wherein R5″ represents{circle around (1)} a C6-14 aryl group (for example, phenyl group) or{circle around (2)} a 5 to 14 membered heterocyclic group containing 1to 4 heteroatoms of one or two kinds selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms (for example,a 5 to 6 membered heterocyclic group containing 1 to 2 heteroatomsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms such as a pyridyl group);

R2 is a C6-14 aryl group (for example, a phenyl group) or a 5 to 14membered aromatic heterocyclic group containing 1 to 4 heteroatoms ofone or two kinds selected from a nitrogen atom, a sulfur atom and anoxygen atom in addition to carbon atoms (for example, a 5 to 6 memberedaromatic heterocyclic group containing 1 to 2 heteroatoms selected froma nitrogen atom, a sulfur atom and an oxygen atom in addition to carbonatoms such as a pyridyl group);

R3 is a C6-14 aryl group (in particular, a phenyl group) optionallysubstituted with 1 or 2 C1-6 alkyl (for example, methyl) or C1-6 alkoxy(for example, methoxy);

X is a sulfur atom;

Y is O, NH or S;

Z is a bond or a C1-6 alkylene group (in particular, a C1-3 alkylenegroup optionally having oxo, such as methylene, ethylene and the like)optionally having oxo.

Genus II Description

Compounds of Genus II can be prepared according to the disclosure ofU.S. Pat. No. 7,115,746, which is herein incorporated herein byreference in its entirety.

Genus II is characterized by compounds of Formula (II):

or stereoisomers thereof, isotopically-enriched compounds thereof,prodrugs thereof, solvates thereof, and pharmaceutically acceptablesalts thereof;wherein:Ar₁ and Ar₂ are each independently aryl or heteroaryl optionally fusedto a saturated or unsaturated 5-8 membered ring having 0-4 heteroatoms,provided that Ar₁ or Ar₂ is heteroaryl;

-   -   wherein the aryl or heteroaryl is optionally substituted with        one or more substituents independently selected from halo; C₁-C₆        aliphatic optionally substituted with —N(R′)₂, —OR′, —CO₂R′,        —C(O)N(R′)₂, —OC(O)N(R′)₂, —NR′CO₂R′, —NR′C(O)R′, —SO₂N(R′)₂,        —N═CH—N(R′)₂, or —OPO₃H₂; C₁-C₆ alkoxy optionally substituted        with —N(R′)₂, —OR′, —CO₂R′, —C(O)N(R′)₂, —OC(O)N(R′)₂,        —NR′CO₂R′, —NR′C(O)R′, —SO₂N(R′)₂, —N═CH—N(R′)₂, or —OPO₃H₂;        —Ar₃; —CF₃; —OCF₃; —OR′; —SR′; —SO₂N(R′)₂; —OSO₂R′; —SCF₃; —NO₂;        —CN; —N(R′)₂; —CO₂R′; —CO₂N(R′)₂; —C(O)N(R′)₂; —NR′C(O)R′;        —NR′CO₂R′; —NR′C(O)C(O)R′; —NR′SO₂R′; —OC(O)R′; —NR′C(O)R²;        —NR′CO₂R²; —NR′C(O)C(O)R²; —NR′C(O)N(R′)₂; —OC(O)N(R′)₂;        —NR′SO₂R²; —NR′R²; —N(R²)₂, —OC(O)R²; —OPO₃H₂; and —N═CH—N(R′)₂;

-   R′ is selected from hydrogen; C₁-C₆ aliphatic; or a 5-6 membered    carbocyclic or heterocyclic ring system optionally substituted with    1 to 3 substituents independently selected from halo, C₁-C₆ alkoxy,    cyano, nitro, amino, hydroxy, and C₁-C₆ aliphatic;

-   R² is a C₁-C₆ aliphatic optionally substituted with —N(R′)₂, —OR′,    —CO₂R′, —C(O)N(R′)₂ or —SO₂N(R′)₂; or a carbocyclic or heterocyclic    ring system optionally substituted with —N(R′)₂, —OR′, —CO₂R′,    —C(O)N(R′)₂ or —SO₂N(R′)₂;

-   Ar₃ is an aryl or heteroaryl ring system optionally fused to a    saturated or unsaturated 5-8 membered ring having 0-4 heteroatoms,    -   wherein Ar₃ is optionally substituted at one or more ring atoms        with one or more substituents independently selected from halo;        C₁-C₆ aliphatic optionally substituted with —N(R′)₂, —OR′,        —CO₂R′, —C(O)N(R′)₂, —OC(O)N(R′)₂, —NR′CO₂R′, —NR′C(O)R′,        —SO₂N(R′)₂, —N═C—N(R′)₂, or —OPO₃H₂; C₁-C₆ alkoxy optionally        substituted with —N(R′)₂, —OR′, —CO₂R′, —C(O)N(R′)₂,        —OC(O)N(R′)₂, —SO₂N(R′)₂, —NR′CO₂R, —NR′C(O)R′, —N═C—N(R′)₂, or        —OPO₃H₂; —CF₃; —OCF₃; —OR′; —SR′; —SO₂N(R′)₂; —OSO₂R′; —SCF₃;        —NO₂; —CN; —N(R′)₂; —CO₂R′; —CO₂N(R′)₂; —C(O)N(R′)₂; —NR′C(O)R′;        —NR′CO₂R′; —NR′C(O)C(O)R′; —NR′SO₂R′; —OC(O)R′; —NR′C(O)R²;        —NR′CO₂R²; —NR′C(O)C(O)R²; —NR′C(O)N(R′)₂; —OC(O)N(R′)₂;        —NR′SO₂R²; —NR′R²; —N(R²)₂; —OC(O)R²; —OPO₃H₂; and —N═C—N(R′)₂;        and

-   Y is —C(O)—NH₂.

In one embodiment, the p38 kinase inhibitor is2-(2,4-difluorophenyl)-6-(1-(2,6-difluorophenyl)ureido)nicotinamide(“VX-702”), Formula II′.

Genus II Definitions

As used herein, the following definitions shall apply unless otherwiseindicated. The phrase “optionally substituted” is used interchangeablywith the phrase “substituted or unsubstituted.” Also, combinations ofsubstituents are permissible only if such combinations result inchemically stable compounds. In addition, unless otherwise indicated,functional group radicals are independently selected.

The term “aliphatic” as used herein means straight-chain or branchedC₁-C₁₂hydrocarbon chain that is completely saturated or that containsone or more units of unsaturation. The term “aliphatic” also includes amonocyclic C₃-C₈hydrocarbon or bicyclic C₈-C₁₂ hydrocarbon that iscompletely saturated or that contains one or more units of unsaturation,but which is not aromatic (said cyclic hydrocarbon chains are alsoreferred to herein as “carbocycle” or “cycloalkyl”), that has a singlepoint of attachment to the rest of the molecule wherein any individualring in said bicyclic ring system has 3-7 members. For example, suitablealiphatic groups include, but are not limited to, linear or branchedalkyl, alkenyl, alkynyl groups and hybrids thereof such as(cycloalkyl)alkyl, (cycloalkenyl)alkyl) or (cycloalkyl)alkenyl.

The terms “alkyl”, “alkoxy”, “hydroxyalkyl”, “alkoxyalkyl”, and“alkoxycarbonyl”, used alone or as part of a larger moiety includes bothstraight and branched chains containing one to twelve carbon atoms. Theterms “alkenyl” and “alkynyl” used alone or as part of a larger moietyshall include both straight and branched chains containing two to twelvecarbon atoms, wherein an alkenyl comprises at least one double bond andan alkynyl comprises at least one triple bond.

The term “chemically stable” or “chemically feasible and stable”, asused herein, refers to a compound structure that renders the compoundsufficiently stable to allow manufacture and administration to a mammalby methods known in the art. Typically, such compounds are stable attemperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

The term “haloalkyl”, “haloalkenyl”, and “haloalkoxy”, means alkyl,alkenyl, or alkoxy, as the case may be, substituted with one or morehalogen atoms. The term “halogen” means F, Cl, Br, or I.

The term “heteroatom” means N, O, or S and shall include any oxidizedform of nitrogen and sulfur, and the quaternized form of any basicnitrogen.

The term “amine” or “amino” used alone or as part of a larger moiety,refers to a trivalent nitrogen, which may be primary or which may besubstituted with 1-2 aliphatic groups.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic,bicyclic, and tricyclic carbocyclic ring systems having a total of fiveto fourteen members, where at least one ring in the system is aromaticand wherein each ring in the system contains 3 to 8 ring members. Theterm “aryl” may be used interchangeably with the term “aryl ring”.

The term “heterocycle”, “heterocyclyl”, or “heterocyclic” as used hereinmeans non-aromatic, monocyclic, bicyclic, or tricyclic ring systemshaving five to fourteen ring members in which one or more of the ringmembers is a heteroatom, wherein each ring in the system contains 3 to 7ring members.

One having ordinary skill in the art will recognize that the maximumnumber of heteroatoms in a stable, chemically feasible heterocyclic orheteroaromatic ring is determined by the size of the ring, degree ofunsaturation, and valence of the heteroatoms. In general, a heterocyclicor heteroaromatic ring may have one to four heteroatoms so long as theheterocyclic or heteroaromatic ring is chemically feasible and stable.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclicand tricyclic ring systems having a total of five to fourteen ringmembers, and wherein at least one ring in the system is aromatic, atleast one ring in the system contains one or more heteroatoms, and eachring in the system contains 3 to 7 ring members. The term “heteroaryl”may be used interchangeably with the term “heteroaryl ring” or the term“heteroaromatic”.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) orheteroaryl (including heteroarylalkyl and heteroarylalkoxy and the like)group may contain one or more substituents. Suitable substituents on theunsaturated carbon atom of an aryl, heteroaryl, aralkyl, orheteroaralkyl group are selected from halogen; haloalky; —CF₃; —R⁴;—OR⁴; —SR⁴; 1,2-methylenedioxy; 1,2-ethylenedioxy; protected OH (such asacyloxy); phenyl (Ph); Ph substituted with R⁴; —OPh; —OPh substitutedwith R⁴; —CH₂Ph; —CH₂Ph substituted with R⁴; —CH₂CH₂(Ph); —CH₂CH₂(Ph)substituted with R⁴; —NO₂; CN; N(R′)₂; —NR⁴C(O)R⁴; —NR⁴C(O)N(R⁴)₂;—NR⁴CO₂R⁴; —NR⁴NRC(O)R⁴; —NR⁴C(O)N(R⁴)₂; —NR⁴NR⁴C(O)R⁴;—NR⁴NR⁴C(O)N(R⁴)₂; NR⁴NR⁴CO₂R⁴; —C(O)C(O)R⁴—C(O)CH₂C(O)R′; —CO₂R′;—C(O)R′; —C(O)N(R′)₂; —OC(O)N(R⁴)₂; —SO₂R′; —SO₂N(R′)₂; —S(O)R⁴;—NR⁴SO₂N(R′)₂; —NR⁴SO₂R⁴; —C(═S)N(R′)₂; —C(═NH)—N(R′)₂;—(CH₂)_(y)NHC(O)R⁴; —(CH₂)_(y)R⁴; —(CH₂)_(y)NHC(O)NHR⁴;—(CH₂)_(y)NHC(O)OR⁴; —(CH₂)_(y)NHS(O)R⁴; —(CH₂)_(y)NHSO₂R⁴; or—(CH₂)_(y)NHC(O)CH(V—R⁴)R⁴; wherein each R⁴ is independently selectedfrom hydrogen, optionally substituted C₁₋₆ aliphatic, an unsubstituted5-6 membered heteroaryl or heterocyclic ring, phenyl (Ph), —O-Ph, —CH₂(Ph); wherein y is 0-6; and V is a linker group. When R⁴ is C₁₋₆aliphatic, it may be substituted with one or more substituents selectedfrom —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂, —S(O) (C₁₋₄aliphatic), —SO₂(C₁₋₄ aliphatic), halogen, —(C₁₋₄ aliphatic), —OH,—O—(C₁₋₄ aliphatic), —NO₂, —CN, —CO₂H, —CO₂(C₁₋₄ aliphatic), —O-(haloC₁₋₄ aliphatic), or -halo(C₁₋₄ aliphatic); wherein each C₁₋₄ aliphaticis unsubstituted.

The term “linker group” or “linker” means an organic moiety thatconnects two parts of a compound. Linkers are comprised of —O—, —S—,—NR*—, —C(R*)₂—, —C(O), or an alkylidene chain. The alkylidene chain isa saturated or unsaturated, straight or branched, C₁₋₆ carbon chainwhich is optionally substituted, and wherein up to two non-adjacentsaturated carbons of the chain are optionally replaced by —C(O)—,—C(O)C(O)—, —C(O)NR*—, —C(O)NR*NR*—, NR*NR*—, —NR*C(O)—, —S—, —SO—,—SO₂—, —NR*—, —SO₂NR*—, or —NR*SO₂—; wherein R* is selected fromhydrogen or aliphatic. Optional substituents on the alkylidene chain areas described below for an aliphatic group.

An aliphatic group or a non-aromatic heterocyclic ring may contain oneor more substituents. Suitable substituents on the saturated carbon ofan aliphatic group or of a non-aromatic heterocyclic ring are selectedfrom those listed above for the unsaturated carbon of an aryl orheteroaryl group and the following: ═O, ═S, ═NNHR⁵, ═NN(R⁵)₂, ═NR⁵,—OR⁵, ═NNHC(O)R⁵, ═NNHCO₂R⁵, ═NNHSO₂R⁵, or ═NR⁵, where each R⁵ isindependently selected from hydrogen or a optionally substituted C₁₋₆aliphatic. When R⁵ is C₁₋₆ aliphatic, it may be substituted with one ormore substituents selected from —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄aliphatic)₂, halogen, —OH, —O—(C₁₋₄ aliphatic), —NO₂, —CN, —CO₂H,—CO₂(C₁₋₄ aliphatic), —O-(halo C₁₋₄ aliphatic), or (halo C₁₋₄aliphatic); wherein each C₁₋₄ aliphatic is unsubstituted.

Substituents on the nitrogen of a non-aromatic heterocyclic ring areselected from —R⁶, —N(R⁶)₂, —C(O)R⁶, —CO₂R⁶, —C(O)C(O)R⁶,—C(O)CH₂C(O)R⁶, —SO₂R⁶, SO₂N(R⁶)₂, —C(═S)N(R′)₂, —C(═NH)—N(R′)₂, or—NRSO₂R; wherein each R⁶ is independently selected from hydrogen, anoptionally substituted C₁₋₆ aliphatic, optionally substituted phenyl(Ph), optionally substituted —O-Ph, optionally substituted —CH₂ (Ph), oran unsubstituted 5-6 membered heteroaryl or heterocyclic ring. When R⁶is a C₁₋₆ aliphatic group or a phenyl ring, it may be substituted withone or more substituents selected from —NH₂, —NH(C₁₋₄aliphatic), —N(C₁₋₄aliphatic)₂, halogen, —(C₁₋₄ aliphatic), —OH, —O—(C₁₋₄ aliphatic), —NO₂,—CN, —CO₂H, —CO₂(C₁₋₄ aliphatic), —O-halo(C₁₋₄ aliphatic), or (haloC₁₋₄aliphatic); wherein each C₁₋₄ aliphatic is unsubstituted.

Genus III Description

Compounds of Genus III can be prepared according to the disclosure ofU.S. Pat. No. 6,696,566, which is herein incorporated herein byreference in its entirety.

Genus III is characterized by compounds of Formula III:

or stereoisomers thereof, isotopically-enriched compounds thereof,prodrugs thereof, solvates thereof, and pharmaceutically acceptablesalts thereof;wherein:

-   R¹ is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl,    heteroaralkyl, cycloalkyl, cycloalkylalkyl, heteroalkylsubstituted    cycloalkyl, heterosubstituted cycloalkyl, heteroalkyl, cyanoalkyl,    heterocyclyl, heterocyclylalkyl, R¹²—SO₂-heterocycloamino,    —Y¹(O)—Y²—R¹¹, (heterocyclyl)(cycloalkyl)alkyl, or    (heterocyclyl)(heteroaryl)alkyl;    -   wherein:        -   R¹² is haloalkyl, aryl, aryalkyl, heteroaryl or            heteroaralkyl,        -   Y¹ and Y² are each independently absent or an alkylene            group, and        -   R¹¹ is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, amino,            monoalkylamino or dialkylamino,-   W is NR²;-   X¹ is O, NR⁴, S, or CR⁵R⁶, or C═O,    -   wherein:        -   R⁴ is hydrogen or alkyl, and        -   R⁵ and R⁶ are each independently hydrogen or alkyl;-   X² is O or NR⁷,    -   wherein R⁷ is hydrogen or alkyl;-   Ar¹ is aryl or heteroaryl;-   R² is hydrogen alkyl, acyl, alkoxycarbonyl, aryloxycarbonyl,    heteroalkylcarbonyl, heteroalkyloxycarbonyl or —R²¹—R²²,    -   wherein:        -   R²¹ is alkylene or —C(═O)—, and        -   R²² is alkyl or alkoxy;-   R³ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,    haloalkyl, heteroalkyl, cyanoalkyl, alkylene-C(O)—R³¹, amino,    monoalkylamino, dialkylamino, or NR³²Y³—R³³,    -   wherein:        -   R³¹ is hydrogen, alkyl, hydroxy, alkoxy, amino,            monoalkylamino or dialkylamino, and        -   Y³ is —C(O), —C(O)O—, —C(O)N(R³⁴)—, —S(O)₂—, or            —S(O)₂N(R³⁵)—,        -   wherein:            -   R³⁴ is hydrogen or alkyl, and            -   R³³ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,                heteroalkyl or optionally substituted phenyl) or acyl.

In some embodiments, the p38 kinase inhibitor from Genus III is selectedfrom the following:

-   2-amino-6-(2-fluorophenoxy)-8-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(phenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(3-fluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one-   6-(2,4-difluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2-fluorobenzyl)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one;-   6-[(4-fluorophenyl)thiol-]-2-[(4-hydroxycyclohexyl)amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(4-fluorophenoxy)-2-[(4-hydroxycyclohexyl)amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2-fluorobenzyl)-2-[(4-hydroxycyclohexyl)amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2-fluorophenoxy)-2-[(4-methoxycyclohexyl)    amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2-fluorophenoxy)-8-methyl-2-{[1-(methyl    sulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2-fluorophenoxy)-8-(4-fluorophenyl)-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one;-   8-cyclopropyl-6-(2-fluorophenoxy)-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2-chlorophenoxy)-8-methyl-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(4-chlorophenoxy)-8-methyl-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one;-   2-(cyclopropylamino)-6-(2-fluorophenoxy)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   2-(cyclopentylamino)-6-(4-fluorophenoxy)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   2-(cyclopentylamino)-6-(3-fluorophenoxy)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   2-(butylamino)-6-(2-fluorophenoxy)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2-fluorophenoxy)-2-[(2-hydroxyethyl)    amino]-8methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2-fluorophenoxy)-2-(isobutylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2-fluorophenoxy)-2-{[(1S)-1-(hydroxy    methyl)-2-methylpropyl]amino}-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   2-[(2,3-dihydroxypropyl)amino]-6-(2-fluorophenoxy)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2-fluorophenoxy)-8-methyl-2-[(2-piperidin-1-ylethyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one;-   2-[(cyclohexylmethyl)amino]-6-(2-fluorophenoxy)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   2-[(cyclopropylmethyl)amino]-6-(2-fluoro    phenoxy)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2-fluorophenoxy)-2-[(2-methoxyethyl)amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   2-{[3-(dimethylamino)propyl]amino}-6-(2-fluorophenoxy)-8-methylpyrido[2,3-d]pyrimidin-7(8H1)-one;-   6-(2-fluorophenoxy)-8-methyl-2-{[3-(2-oxopyrrolidin-1-yl)propyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one;-   N-(2-{[6-(2-fluorophenoxy)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl)acetamide;-   6-(2-fluorophenoxy)-8-methyl-2-[(2-pyridin-3-ylethyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one;-   ethyl    N-[6-(2-fluorophenoxy)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]-β-alaninate;-   6-(2-fluorophenoxy)-2-[(3-methoxypropyl)amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(4-chlorophenoxy)-2-{[(1S)-2-hydroxy-1,2-dimethylpropyl]amino}-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2,4-difluorophenoxy)-2-{[(1S)-2-hydroxy-1,2-dimethylpropyl]amino}-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2-fluorobenzyl)-2-{[(1S)-2-hydroxy-1,2-dimethylpropyl]amino}-8-methylpyrido[2,3-d]pyrimidin-7(8TH-one;    6-(2-fluorophenoxy)-8-methyl-2-[(1-oxidotetrahydro-2H-thiopyran-4-yl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one;

2-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-6-(2-fluorophenoxy)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;

-   6-(2,4-difluorophenoxy)-8-methyl-2-[(1-oxidotetrahydro-2H-thiopyran-4-yl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one;-   2-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-6-(2,4-difluorophenoxy)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2,6-difluorophenoxy)-2-{[1-(hydroxy    methyl)butyl]amino}-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2,6-difluorophenoxy)-2-[(2-hydroxy-1,1-dimethylethyl)amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2-fluorophenoxy)-2-{[1-(hydroxymethyl)    cyclopentyl]amino}-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2-fluorophenoxy)-2-{[1-(hydroxymethyl)-3-(methylthio)propyl]amino}-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   2-(benzylamino)-6-(4-fluorophenoxy)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   2-(benzylamino)-6-(4-fluorobenzyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2-fluorophenoxy)-8-methyl-2-[(1-phenyl    propyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2-fluorophenoxy)-8-methyl-2-[(pyridin-2-ylmethyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2-fluorophenoxy)-2-[(3-furylmethyl)    amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   8-methyl-6-phenoxy-2-[(2-phenylethyl)    amino]pyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2-chlorophenoxy)-8-methyl-2-[(2-phenyl    ethyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one;-   Ethyl    4-{[6-(2,4-difluorophenoxy)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}piperidine-1-carboxylate;-   8-methyl-2-{[3-(4-methylpiperazin-1-yl)propyl]amino}-6-phenoxypyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2-chlorophenoxy)-8-methyl-2-{[3-(4-methylpiperazin-1-yl)propyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one;-   2-anilino-6-(4-fluorobenzyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(4-fluorophenoxy)-2-[(4-fluorophenyl)    amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2,6-dichlorophenoxy)-2-[(4-fluorophenyl)    amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(4-fluorobenzyl)-2-[(4-fluorophenyl)amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   2-{[4-(2-hydroxyethyl)phenyl]amino}-8-methyl-6-phenoxypyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2-chlorophenoxy)-2-({4-[2-(diethylamino)    ethoxy]phenyl}amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   2-({4-[2-(diethylamino)ethoxy]phenyl}amino)-6-(4-fluorophenoxy)-8-methylpylido[2,3-d]pyrimidin-7(8H)-one;-   6-(2-fluorophenoxy)-2-[(3-hydroxypyridin-2-yl)amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2-fluorophenoxy)-8-methyl-2-[(5-methylpyridin-2-yl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one;-   2-(benzylthio)-6-(4-fluorophenoxy)pyrido[2,3-d]pyrimidin-7-amine;-   6-(2,4-difluorophenoxy)-2-(benzylthio)pyrido[2,3-d]pyrimidin-7(8H)-one;-   1-tert-Butyl-3-[6-(2,4-difluoro-phenoxy)-2-(tetrahydro-pyran-4-ylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;-   N-[6-(2,4-Difluoro-phenoxy)-2-(tetrahydro-pyran-4-ylamino)-pyrido[2,3-d]pyrimidin-7-yl]-methanesulfonamide;-   6-(2,4-difluorophenoxy)-2-{[(1S)-2-fluoro-1,2-dimethylpropyl]amino}-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2,4-Difluoro-phenoxy)-2-{[(1S)-2-hydroxy-1,2-dimethylpropyl]amino}-8-isopropylpyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2,4-difluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyridin-7(8H)-one;-   8-Amino-6-(2,4-difluoro-phenoxy)-2-(tetrahydro-pyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;-   6-(2,4-Difluoro-phenoxy)-8-isopropylamino-2-(tetrahydro-pyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;-   6-(2,4-Difluoro-phenoxy)-8-[N-methyl-(N-3-methyl-butyl)-amino]-2-(tetrahydro-pyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;-   6-(2,4-Difluoro-phenoxy)-8-N,N-dimethylamino-2-(tetrahydro-pyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;-   6-(2,4-Difluoro-phenylamino)-2-(2-hydroxy-1,1-dimethyl-ethylamino)-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one:-   6-[(2,4-Difluoro-phenyl)-methyl-amino]-8-methyl-2-(tetrahydro-pyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;-   6-(2,4-Difluorophenoxy)-8-ethyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2,4-difluorophenoxy)-8-ethyl-2-(3-hydroxy-tetrahydro-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2,4-Difluoro-phenoxy)-2-(3-hydroxy-1,3-dimethyl-butylamino)-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one;-   6-(2,4-Difluoro-phenoxy)-2-(3-hydroxy-1(S),3-dimethyl-butylamino)-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one;-   6-(2,4-Difluoro-phenoxy)-2-(3-hydroxy-1(R),3-dimethyl-butylamino)-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one;-   6-(2,4-difluorophenoxy)-8-methyl-2-(3-hydroxy-tetrahydro-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2-fluorophenoxy)-2-[(5-hydroxypyrazol-3-yl)amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2-fluorophenoxy)-2-[(pyridin-2-yl-methyl)amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   2-{[(1,5-Dimethyl-1H-pyrazol-4-yl)methyl]amino}-6-(2-fluorophenoxy)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   2-{[(1,3-Dimethyl-1H-pyrazol-4-yl)methyl]amino}-6-(2-fluorophenoxy-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2-fluorophenoxy)-2-{[(3-methyl-isoxazol-5-yl)methyl]amino}-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   2-{[1-(Hydroxymethyl)cyclohexyl]amino}-6-(2-methylbenzyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   2-{[1-(Hydroxymethyl)cyclopentyl]amino}-6-(2-methylbenzyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   6-Benzyl-2-{[1-(hydroxymethyl)cyclopentyl]amino}-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;-   N-[6-(2,4-Difluoro-phenoxy)-8-methyl-7-oxo-4a,7,8,8a-tetrahydro-pyrido[2,3d]pyrimidin-2-y]-N-(tetrahydro-pyran-4-yl)-acetamide;-   ethyl    4-{[6-(2-fluorophenoxy)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}piperidine-1-carboxylate;-   6-(2-fluorophenoxy)-8-methyl-2-{[(1-benzylsulfonyl)piperidiny-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2-methyl-4-fluorophenoxy)-8-methyl-2-{[(1-benzylsulfonyl)piperidiny-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one;-   6-(2,4-difluorophenoxy)-8-methyl-2-(N1-methylsulfonyl)-1,3-diaminopentane)    pyrido[2,3-d]pyrimdin-7(8H)-one;-   6-(2,4-difluorophenoxy)-8-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one    (“R1487”), Formula III′a; and-   6-(2,4-difluorophenoxy)-2-((1,5-dihydroxypentan-3-yl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one    (“Pamapimod”), Formula III′b.

In one embodiment, the p38 kinase inhibitor is6-(2,4-difluorophenoxy)-8-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one(“R1487”), Formula III′a.

In one embodiment, the p38 kinase inhibitor is6-(2,4-difluorophenoxy)-2-((1,5-dihydroxypentan-3-yl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one(“Pamapimod”), Formula III′b.

Genus III Definitions

“Acyl” means a radical —C(O)R, where R is hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, phenyl or phenylalkyl wherein alkyl, cycloalkyl,cycloalkylalkyl, and phenylalkyl are as defined herein. Representativeexamples include, but are not limited to formyl, acetyl,cylcohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl,and the like.

“Acylamino” means a radical —NR′C(O)R, where R′ is hydrogen or alkyl,and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl orphenylalkyl wherein alkyl, cycloalkyl, cycloalkylalkyl, and phenylalkylare as defined herein. Representative examples include, but are notlimited to formylamino, acetylamino, cylcohexylcarbonylamino,cyclohexylmethylcarbonylamino, benzoylamino, benzylcarbonylamino, andthe like.

“Alkoxy” means a radical —OR where R is an alkyl as defined herein e.g.,methoxy, ethoxy, propoxy, butoxy and the like.

“Alkyl” means a linear saturated monovalent hydrocarbon radical of oneto six carbon atoms or a branched saturated monovalent hydrocarbonradical of three to six carbon atoms, e.g., methyl, ethyl, propyl,2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and the like.

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms, e.g., methylene, ethylene,2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene,and the like.

“Alkylthio” means a radical SR where R is an alkyl as defined abovee.g., methylthio, ethylthio, propylthio, butylthio, and the like.

“Aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbonradical which is optionally substituted independently with one or moresubstituents, preferably one, two or three, substituents preferablyselected from the group consisting of alkyl, hydroxy, alkoxy, haloalkyl,haloalkoxy, Y—C(O)—R (where Y is absent or an alkylene group and R ishydrogen, alkyl, haloalkyl, haloalkoxy, hydroxy, alkoxy, amino,monoalkylamino or dialkylamino), heteroalkyl, heteroalkyloxy,heteroalkylamino, halo, nitro, cyano, amino, monoalkylamino,dialkylamino, alkylsulfonylamino, heteroalkylsulfonylamino, sulfonamido,methylenedioxy, ethylenedioxy, heterocyclyl or heterocyclylalkyl. Morespecifically the term aryl includes, but is not limited to, phenyl,chlorophenyl, methoxyphenyl, 2-fluorophenyl, 2,4-difluorophenyl,1-naphthyl, 2-naphthyl, and the derivatives thereof.

“Aryloxy” means a radical OR where R is an aryl as defined herein e.g.phenoxy.

“Aryloxycarbonyl” means a radical R—C(═O)— where R is aryloxy, e.g.phenoxycarbonyl.

“Cycloalkyl” refers to a saturated monovalent cyclic hydrocarbon radicalof three to seven ring carbons e.g., cyclopropyl, cyclobutyl,cyclohexyl, 4-methyl-cyclohexyl, and the like.

“Cycloalkylalkyl” means a radical —R^(a)R^(b) where R^(a) is an alkylenegroup and R^(b) is cycloalkyl group as defined herein, e.g.,cyclohexylmethyl, and the like.

“Substituted cycloalkyl” means a cycloalkyl radical as defined hereinwith one, two or three (preferably one) ring hydrogen atomsindependently replaced by cyano or —Y—C(O)R (where Y is absent or analkylene group and R is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy,amino, monoalkylamino, dialkylamino, or optionally substituted phenyl).

“Dialkylamino” means a radical —NRR′ where R and R′ independentlyrepresent an alkyl, hydroxyalkyl, cycloalkyl, or cycloalkylalkyl groupas defined herein. Representative examples include, but are not limitedto dimethylamino, methylethylamino, di(1-methylethyl)amino,(methyl)(hydroxymethyl)amino, (cyclohexyl)(methyl)amino,(cyclohexyl)(ethyl)amino, (cyclohexyl)(propyl)amino,(cyclohexylmethyl)(methyl)amino, (cyclohexylmethyl)(ethyl)amino, and thelike.

“Halo” means fluoro, chloro, bromo, or iodo, preferably fluoro andchloro.

“Haloalkyl” means alkyl substituted with one or more same or differenthalo atoms, e.g., —CH₂Cl, —CF₃, —CH₂CF₃, —CH₂CCl₃, and the like.

“Heteroalkyl” means an alkyl radical as defined herein wherein one, twoor three hydrogen atoms have been replaced with a substituentindependently selected from the group consisting of —OR^(a),—N(O)_(n)R^(b)R^(c) (where n is 0 or 1 if R^(b) and R^(c) are bothindependently alkyl, cycloalkyl or cycloalkylalkyl, and 0 if not) and—S(O)_(n)R^(d) (where n is an integer from 0 to 2), with theunderstanding that the point of attachment of the heteroalkyl radical isthrough a carbon atom, wherein R^(a) is hydrogen, acyl, alkoxycarbonyl,alkyl, cycloalkyl, or cycloalkylalkyl; R^(b) and R^(c) are independentlyof each other hydrogen, acyl, alkoxycarbonyl, alkyl, cycloalkyl,cycloalkylalkyl, alkyl sulfonyl, aminosulfonyl, mono- ordi-alkylaminosulfonyl, aminoalkyl, mono- or di-alkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, hydroxyalkylsulfonyl or alkoxyalkylsulfonyl;and when n is 0, R^(d) is hydrogen, alkyl, cycloalkyl, cycloalkylalkylor optionally substituted phenyl, and when n is 1 or 2, R^(d) is alkyl,cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, amino,acylamino, monoalkylamino, or dialkylamino. Representative examplesinclude, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl,2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl,1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl,2-hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl,2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl,aminosulfonylpropyl, methylaminosulfonylmethyl,methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.

“Heteroalkylcarbonyl” means the group R_(a)—C(═O)—, where R_(a) is aheteroalkyl group. Representative examples includeacetyloxymethylcarbonyl, aminomethylcarbonyl,4-acetyloxy-2,2-dimethyl-butan-2-oyl, 2-amino-4-methyl-pentan-2-oyl, andthe like.

“Heteroalkyloxy” means the group R_(a)O—, where R_(a) is a heteroalkylgroup. Representative examples include (Me-C(═O)—O—CH₂—O—, and the like

“Heteroalkyloxycarbonyl” means the group R_(a)—C(═O), where R_(a) is aheteroalkyloxy group. Representative examples include1-acetyloxy-methoxycarbonyl (Me-C(═O)—O—CH₂—O—C(═O)—) and the like

“Heteroaryl” means a monovalent monocyclic or bicyclic radical of 5 to12 ring atoms having at least one aromatic ring containing one, two, orthree ring heteroatoms selected from N, O, or S, the remaining ringatoms being C, with the understanding that the attachment point of theheteroaryl radical will be on an aromatic ring. The heteroaryl ring isoptionally substituted independently with one or more substituents,preferably one or two substituents, selected from alkyl, haloalkyl,heteroalkyl, hydroxy, alkoxy, halo, nitro or cyano. More specificallythe term heteroaryl includes, but is not limited to, pyridyl, furanyl,thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl,pyrrolyl, pyrazolyl, pyrimidinyl, benzofuranyl, tetrahydrobenzofuranyl,isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl,indolyl, isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl,isoquinolyl, benzimidazolyl, benzisoxazolyl or benzothienyl,imidazo[1,2-a]-pyridinyl, imidazo[2,1-b]thiazolyl, and the derivativesthereof.

“Heteroaralkyl” means a radical —R^(a)R^(b) where R^(a) is an alkylenegroup and R^(b) is a heteroaryl group as defined herein, e.g.,pyridin-3-ylmethyl, imidazolylethyl, pyridinylethyl,3-(benzofuran-2-yl)propyl, and the like.

“Heteroalkylsubstituted cycloalkyl” means a cycloalkyl radical asdefined herein wherein one, two or three hydrogen atoms in thecycloalkyl radical have been replaced with a heteroalkyl group with theunderstanding that the heteroalkyl radical is attached to the cycloalkylradical via a carbon-carbon bond. Representative examples include, butare not limited to, 1-hydroxymethylcyclopentyl,2-hydroxymethylcyclohexyl, and the like.

“Heterosubstituted cycloalkyl” means a cycloalkyl radical as definedherein wherein one, two or three hydrogen atoms in the cycloalkylradical have been replaced with a substituent independently selectedfrom the group consisting of hydroxy, alkoxy, amino, acylamino,monoalkylamino, dialkylamino, oxo (C═O), imino, hydroximino (═NOH),NR′SO₂R^(d) (where R′ is hydrogen or alkyl and R^(d) is alkyl,cycloalkyl, hydroxyalkyl, amino, monoalkylamino or dialkylamino),—X—Y—C(O)R (where X is O or NR′, Y is alkylene or absent, R is hydrogen,alkyl, haloalkyl, alkoxy, amino, monoalkylamino, dialkylamino, oroptionally substituted phenyl, and R′ is H or alkyl), or —S(O)_(n)R(where n is an integer from 0 to 2) such that when n is 0, R ishydrogen, alkyl, cycloalkyl, cycloalkylalkyl optionally substitutedphenyl or thienyl, and when n is 1 or 2, R is alkyl, cycloalkyl,cycloalkylalkyl, optionally substituted phenyl, thienyl, amino,acylamino, monoalkylamino or dialkylamino. Representative examplesinclude, but are not limited to, 2-, 3-, or 4-hydroxycyclohexyl, 2-, 3-,or 4-aminocyclohexyl, 2-, 3-, or 4-methanesulfonamido-cyclohexyl, andthe like, preferably 4-hydroxycyclohexyl, 2-aminocyclohexyl or4-methanesulfonamido-cyclohexyl.

“Heterosubstituted cycloalkyl-alkyl” means a radical R^(a)R^(b)— whereR^(a) is a heterosubstituted cycloalkyl radical and R^(b) is an alkyleneradical.

“Heterocycloamino” means a saturated monovalent cyclic group of 4 to 8ring atoms, wherein one ring atom is N and the remaining ring atoms areC. Representative examples include piperidine and pyrrolidine.

“Heterocyclyl” means a saturated or unsaturated non-aromatic cyclicradical of 3 to 8 ring atoms in which one or two ring atoms areheteroatoms selected from N, O, or S(O)_(n) (where n is an integer from0 to 2), the remaining ring atoms being C, where one or two C atoms mayoptionally be replaced by a carbonyl group. The heterocyclyl ring may beoptionally substituted independently with one, two, or threesubstituents selected from alkyl, haloalkyl, heteroalkyl, halo, nitro,cyano, cyanoalkyl, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino,aralkyl, —(X)_(n)—C(O)R (where X is O or NR′, n is 0 or 1, R ishydrogen, alkyl, haloalkyl, hydroxy (when n is 0), alkoxy, amino,monoalkylamino, dialkylamino, or optionally substituted phenyl, and R′is H or alkyl), -alkylene-C(O)R^(a) (where R^(a) is alkyl, OR or NR′R″and R is hydrogen, alkyl or haloalkyl, and R′ and R″ are independentlyhydrogen or alkyl), or —S(O)_(n)R (where n is an integer from 0 to 2)such that when n is 0, R is hydrogen, alkyl, cycloalkyl, orcycloalkylalkyl, and when n is 1 or 2, R is alkyl, cycloalkyl,cycloalkylalkyl, amino, acylamino, monoalkylamino, dialkylamino orheteroalkyl. More specifically the term heterocyclyl includes, but isnot limited to, tetrahydropyranyl, piperidino, N-methylpiperidin-3-yl,piperazino, N-methylpyrrolidin-3-yl, 3-pyrrolidino, morpholino,thiomorpholino, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide,4-(1,1-dioxo-tetrahydro-2H-thiopyranyl), pyrrolinyl, imidazolinyl,N-methanesulfonyl-piperidin-4-yl, and the derivatives thereof.

“Heterocyclylalkyl” means a radical —R^(a)R^(b) where R^(a) is analkylene group and R^(b) is a heterocyclyl group as defined above, e.g.,tetrahydropyran-2-ylmethyl, 2- or 3-piperidinylmethyl,3-(4-methyl-piperazin-1-yl)propyl and the like.

“(Heterocyclyl)(cycloalkyl)alkyl” means an alkyl radical wherein twohydrogen atoms have been replaced with a heterocyclyl group and acycloalkyl group.

“(Heterocyclyl)(heteroaryl)alkyl” means an alkyl radical wherein twohydrogen atoms have been replaced with a heterocycyl group and aheteroaryl group. “Heterocyclyl spiro cycloalkyl” means a spiro radicalconsisting of a cycloalkyl ring and a heterocyclic ring with each ringhaving 5 to 8 ring atoms and the two rings having only one carbon atomin common, with the understanding that the point of attachment of theheterocyclyl spiro cycloalkyl radical is via the cycloalkyl ring. Thespiro radical is formed when two hydrogen atoms from the same carbonatom of the cycloalkyl radical are replaced with a heterocyclyl group asdefined herein, and may be optionally substituted with alkyl, hydroxy,hydroxyalkyl, or oxo. Examples include, but are not limited to, forexample, 1,4-dioxaspiro[4.5]decan-8-yl, 1,3-diazaspiro[4.5]decan-8-yl,2,4-dione-1,3-diaza-spiro[4.5]decan-8-yl,1,5-dioxa-spiro[5.5]undecan-9-yl,(3-hydroxymethyl-3-methyl)-1,5-dioxa-spiro[5.5]undecan-9-yl, and thelike.

“Hydroxyalkyl” means an alkyl radical as defined herein, substitutedwith one or more, preferably one, two or three hydroxy groups, providedthat the same carbon atom does not carry more than one hydroxy group.Representative examples include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl,2,3-dihydroxypropyl and 1-(hydroxymethyl)-2-hydroxyethyl. Accordingly,as used herein, the term “hydroxyalkyl” is used to define a subset ofheteroalkyl groups.

“Monoalkylamino” means a radical —NHR where R an alkyl, hydroxyalkyl,cycloalkyl, or cycloalkylalkyl group as defined above, e.g.,methylamino, (1-methylethyl)amino, hydroxymethylamino, cyclohexylamino,cyclohexylmethylamino, cyclohexylethylamino, and the like.

“Optionally substituted phenyl” means a phenyl ring which is optionallysubstituted independently with one or more substituents, preferably oneor two substituents selected from the group consisting of alkyl,hydroxy, alkoxy, haloalkyl, haloalkoxy, heteroalkyl, halo, nitro, cyano,amino, methylenedioxy, ethylenedioxy, and acyl.

Genus IV Description

Compounds of Genus IV can be prepared according to the disclosure of US2009/0042856, which is herein incorporated herein by reference in itsentirety.

Genus IV is characterized by compounds of Formula IV:

or stereoisomers thereof, isotopically-enriched compounds thereof,prodrugs thereof, solvates thereof, and pharmaceutically acceptablesalts thereof;wherein:

-   R¹ is selected from the group consisting of hydrogen, substituted or    unsubstituted lower alkyl and substituted or unsubstituted aryl;-   R² is selected from the group consisting of substituted or    unsubstituted aryl and substituted or unsubstituted heteroaryl;-   R³ is lower alkyl;-   p is 0, 1 or 2;-   is a single or double bond; and-   R⁶ and R⁷ are taken together to form a group of the Formula:

-   -   wherein:        -   R⁸ is hydrogen, and        -   X is oxygen or N—R⁹, in which R⁹ is hydrogen, substituted or            unsubstituted lower alkanoyl or substituted or unsubstituted            lower alkyl; or            -   R⁸ and R⁹ may be taken together to form a bond; and        -   m and n are each independently 0, 1 or 2;

-   R¹⁰ and R¹² are each independently selected from the group    consisting of hydrogen, halogen, hydroxy, formyl, cyano, substituted    or unsubstituted lower alkyl, substituted or unsubstituted amino,    substituted or unsubstituted lower alkoxy, saturated cyclic amino,    substituted or unsubstituted carbamoyl, carboxy, substituted or    unsubstituted lower alkoxycarbonyl, and substituted or unsubstituted    acyloxy, or    -   R⁹ and R¹⁰ may be taken together to form lower alkylene or a        bond; and

-   R¹¹, R¹³ and R¹⁴ are each independently selected from the group    consisting of hydrogen, halogen, substituted or unsubstituted lower    alkyl, carboxy, and substituted or unsubstituted lower    alkoxycarbonyl, or    -   R¹⁰ and R¹¹ or R¹² and R¹³ are taken together to form oxo,        hydroxyimino, substituted or unsubstituted lower alkylene in        which one or more carbon(s) may be replaced by hetero atom(s),        or substituted or unsubstituted lower alkylidene, or    -   R¹¹ and R¹² or R¹³ and R¹⁴ may be taken together to form a bond;        and

-   provided that when n=1 and R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ are    simultaneously hydrogen, then R⁹ is substituted or unsubstituted    lower alkyl or substituted or unsubstituted lower alkanoyl.

In one embodiment, the p38 kinase inhibitor from Genus IV is selectedfrom the following:

-   6-{2-(2,4-Difluorophenyl)-6-[(dimethylamino)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)-3    (2H)-pyridazinone;-   6-{2-(2,4-Difluorophenyl)-6-[(dimethylamino)methyl]pyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)-3    (2H)-pyridazinone;-   6-[1-Ethyl-6-(4-fluorophenyl)-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl]-2-(2-methylphenyl)-3(2H)-pyridazinone;-   6-[2-(4-Fluorophenyl)-6,6-bis(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]-2-(2-methylphenyl)pyridazin-3(2H)-one;-   6-[2-(2,4-Difluorophenyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-2-(2-methylphenyl)pyridazin-3(2H)-one;-   6-{2-(4-Fluorophenyl)-6-[(4-methylpiperazin-1-yl)methyl]-4,5,6,7-tetrahydropyrazolo[5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one dihydrochloride;-   6-{2-(2,4-difluorophenyl)-6-[(dimethylamino)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)-4,5-dihydropyridazin-3    (2H)-one;-   N-cyclopropyl-2-(4-fluorophenyl)-3-[1-(2-methylphenyl)-6-oxo-1,6-dihydropyridazin-3-yl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-6-carboxamide;-   6-[6,6-Difluoro-2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]-2-(2-methylphenyl)pyridazin-3(2H)-one;-   6-{6-[(tert-Butylamino)methyl]-2-(2,4-difluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   6-[1-Acetyl-2′-(4-fluorophenyl)-4′,5′-dihydrospiro[piperidine-4,6′-pyrazolo[1,5-a]pyrimidin]-3′-yl]-2-(2-methylphenyl)pyridazin-3(2H)-one;-   6-[(5S)-2-(4-Fluorophenyl)-5-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]-2-(2-methylphenyl)pyridazin-3(2H)-one;-   6-[(5S)-2-(4-Fluorophenyl)-5-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]-2-(2-methylphenyl)pyridazin-3(2H)-one;-   Ethyl    3-(4-fluorophenyl)-2-[1-(2-methylphenyl)-6-oxo-1,6-dihydropyridazin-3-yl]-3-oxopropanoate;-   6-(5-Isopropyl-2-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2-(2-methylphenyl)pyridazin-3(2H)-one;-   6-[2-(4-Fluorophenyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]-2-(2-methylphenyl)-3(2H)-pyridazinone;-   6-[2-(4-Fluorophenyl)-6-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]-2-(2-methylphenyl)-3(2H)-pyridazinone;-   6-[2-(2,4-Difluorophenyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]-2-(2-methylphenyl)pyridazin-3(2H)-one;-   6-[2′-(4-Fluorophenyl)-2,3,4′,5,5′,6-hexahydrospiro[pyran-4,6′-pyrazolo[1,5-a]pyrimidin]-3′-yl]-2-(2-methylphenyl)pyridazin-3(2H)-one;-   6-[2′-(4-Fluorophenyl)-4′,5′-dihydrospiro[1,3-dioxolane-2,6′-pyrazolo[1,5-a]pyrimidin]-3′-yl]-2-(2-methylphenyl)pyridazin-3(2H)-one;-   6-[(6R)-2-(4-Fluorophenyl)-6-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]-2-(2-methylphenyl)pyridazin-3(2H)-one;-   6-[(5S)-2-(4-fluorophenyl)-5-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-2-(2-methylphenyl)pyridazin-3(2H)-one;-   6-[(5S)-2-(4-fluorophenyl)-5-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]-2-(2-methylphenyl)pyridazin-3(2H)-one;-   6-[2-(4-Fluorophenyl)-6,6-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]-2-(2-methylphenyl)pyridazin-3(2H)-one;-   (+)-6-[2-(4-Fluorophenyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]-2-(2-methylphenyl)pyridazin-3(2H)-one;-   (−)-6-[2-(4-Fluorophenyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (+)-6-{2-(4-Fluorophenyl)-6-[(dimethylamino)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (−)-6-{2-(4-Fluorophenyl)-6-[(dimethylamino)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (+)-6-{2-(3-Methylphenyl)-6-[(dimethylamino)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (−)-6-(2-(3-Methylphenyl)-6-[(dimethylamino)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (+)-6-{2-(2-Chloro-4-fluorophenyl)-6-[(dimethylamino)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (−)-6-{2-(2-Chloro-4-fluorophenyl)-6-[(dimethylamino)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (+)-6-{2,5-Difluorophenyl)-6-[(dimethylamino)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (−)-6-(2-(2,5-Difluorophenyl)-6-[(dimethylamino)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (+)-6-{2-(2,4-Difluorophenyl)-6-[(diethylamino)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (−)-6-{2-(2,4-Difluorophenyl)-6-[(diethylamino)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (+)-6-{2-(4-Fluorophenyl)-6-[(di ethyl    amino)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (−)-6-{2-(4-Fluorophenyl)-6-[(diethylamino)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (+)-6-{2-(3-Methylphenyl)-6-[(dimethylamino)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (−)-6-{2-(3-Methylphenyl)-6-[(di ethyl    amino)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (+)-6-{2-(2-Chloro-4-fluorophenyl)-6-[(diethylamino)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (−)-6-{2-(2-Chloro-4-fluorophenyl)-6-[(diethylamino)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (+)-6-{2,5-Difluorophenyl)-6-[(diethylamino)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (−)-6-{2-(2,5-Difluorophenyl)-6-[(diethylamino)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (+)-6-(2-(2,4-Difluorophenyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (−)-6-[2-(2,4-Difluorophenyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (+)-6-[2-(3-Methylphenyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (−)-6-[2-(3-Methylphenyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (+)-6-[2-(2,5-Difluorophenyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (−)-6-[2-(2,5-Difluorophenyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (+)-6-[2-(2-Chloro-4-fluorophenyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (−)-6-[2-(2-Chloro-4-fluorophenyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (+)-6-{2-(4-Fluorophenyl)-6-[(methylamino)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (−)-6-{2-(4-Fluorophenyl)-6-[(methylamino)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (+)-6-{2-(2,4-Difluorophenyl)-6-[(methylamino)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (−)-6-{2-(2,4-Difluorophenyl)-6-[(methylamino)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (+)-6-{2-(2,5-Difluorophenyl)-6-[(methylamino)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (−)-6-{2-(2,5-Difluorophenyl)-6-[(methylamino)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (+)-6-{2-(3-Methylphenyl)-6-[(methyl    amino)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (−)-6-{2-(3-Methylphenyl)-6-[(methyl    amino)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (+)-6-{2-(2-Chloro-4-fluorophenyl)-6-[(methylamino)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (−)-6-{2-(2-Chloro-4-fluorophenyl)-6-[(methylamino)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (+)-6-{6-[(tert-Butylamino)methyl]-2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (−)-6-{6-[(tert-Butylamino)methyl]-2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (+)-6-{6-[(tert-Butylamino)methyl]-2-(2,4-difluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (−)-6-{6-[(tert-Butylamino)methyl]-2-(2,4-difluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (+)-6-{6-[(tert-Butylamino)methyl]-2-(2,5-difluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (−)-6-(6-[(tert-Butylamino)methyl]-2-(2,5-difluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (+)-6-{6-[(tert-Butylamino)methyl]-2-(3-methylphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (−)-6-{6-[(tert-Butylamino)methyl]-2-(3-methylphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (+)-6-{2-(4-Fluorophenyl)-6-[(4-methylpiperazin-1-yl)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (−)-6-{2-(4-Fluorophenyl)-6-[(4-methylpiperazin-1-yl)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (+)-6-{2-(2,4-Difluorophenyl)-6-[(4-methylpiperazin-1-yl)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (−)-6-{2-(2,4-Difluorophenyl)-6-[(4-methylpiperazin-1-yl)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (+)-6-{2-(2,5-Difluorophenyl)-6-[(4-methylpiperazin-1-yl)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (−)-6-{2-(2,5-Difluorophenyl)-6-[(4-methylpiperazin-1-yl)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (+)-6-{2-(3-Methylphenyl)-6-[(4-methylpiperazin-1-yl)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (−)-6-{2-(3-Methylphenyl)-6-[(4-methylpiperazin-1-yl)methyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl}-2-(2-methylphenyl)pyridazin-3    (2H)-one;-   (+)-2-(4-Fluorophenyl)-3-[1-(2-methylphenyl)-6-oxo-1,6-dihydropyridazin-3-yl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-6-carbonitrile;-   (−)-2-(4-Fluorophenyl)-3-[1-(2-methylphenyl)-6-oxo-1,6-dihydropyridazin-3-yl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-6-carbonitrile;-   (+)-2-(2,4-Difluorophenyl)-3-[1-(2-methylphenyl)-6-oxo-1,6-dihydropyridazin-3-yl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-6-carbonitrile;-   (−)-2-(2,4-Difluorophenyl)-3-[1-(2-methylphenyl)-6-oxo-1,6-dihydropyridazin-3-yl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-6-carbonitrile;-   (+)-2-(2,5-Difluorophenyl)-3-[1-(2-methylphenyl)-6-oxo-1,6-dihydropyridazin-3-yl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-6-carbonitrile    (−)-2-(2,5-Difluorophenyl)-3-[1-(2-methylphenyl)-6-oxo-1,6-dihydropyridazin-3-yl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-6-carbonitrile;-   (+)-2-(3-Methylphenyl)-3-[1-(2-methylphenyl)-6-oxo-1,6-dihydropyridazin-3-yl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-6-carbonitrile;-   (−)-2-(3-Methylphenyl)-3-[1-(2-methylphenyl)-6-oxo-1,6-dihydropyridazin-3-yl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-6-carbonitrile;    and-   (R)-6-(2-(4-fluorophenyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-2-(o-tolyl)pyridazin-3(2H)-one    (“AS1940477”), Formula IV′.

In one embodiment, the p38 kinase inhibitor is(R)-6-(2-(4-fluorophenyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-2-(o-tolyl)pyridazin-3(2H)-one(“AS1940477”), Formula IV′.

Genus IV Definitions

Hereinafter the symbols of the Formula (IV) are explained in detail.Throughout the specification and claims, the term “lower” is intended tomean 1 to 6 carbon atom(s) unless otherwise indicated.

Definition of R¹

In the Formula (I), R¹ is selected from the group consisting ofhydrogen, substituted or unsubstituted lower alkyl and substituted orunsubstituted aryl.

Examples of the “lower alkyl” of the “substituted or unsubstituted loweralkyl” for R¹ may include straight or branched (C₁₋₆)alkyl such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl,hexyl, etc., in which the preferred one may be (C₁₋₄)alkyl, and morepreferable one may be methyl, ethyl, propyl, isopropyl, isobutyl, etc.

Examples of the substituents for the “substituted lower alkyl” for R¹may include hydroxy, hydroxy(C₅₋₈)cycloalkyl, (C₅₋₈)cycloalkyl, nitro,nitro (C₅₋₈)cycloalkyl, amido, amido(C₅₋₈)cycloalkyl, sulfonamido,sulfonamido(C₅₋₈)cycloalkyl, ureido, ureido (C₅₋₈)cycloalkyl etc. Thenumber of the substituent may be one; two or more. Where the number ofthe substituent is two or more, the substituents may be the same ordifferent.

Examples of the “aryl” of the “substituted or unsubstituted aryl” for R¹may include (C₆₋₁₄)aryl such as phenyl, naphthyl, indenyl, anthryl,etc., in which the preferred one may be (C₆₋₁₀)aryl, and the morepreferred one may be phenyl, etc.

Examples of the substituents for the “substituted aryl” for R¹ mayinclude lower alkyl [e.g., (C₁₋₄)alkyl (e.g., methyl, ethyl, propyl,butyl, etc.), etc.], (lower)alkylaminosulfonyl [e.g.,(C₁₋₄)alkylaminosulfonyl (e.g., methylaminosulfonyl, ethylaminosulfonyl,propylaminosulfonyl, tert-butylaminosulfonyl, etc.), etc.], aryloxy(e.g., (C₆₋₁₄)aryloxy, etc.), halo(lower)alkyl (e.g., chloromethyl,dichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl,pentachloroethyl, etc.), hydroxy(lower)alkyl (e.g., hydroxy(C₁₋₄)alkyl,etc.), lower alkanoyl (e.g., (C₁₋₄)alkyl-carbonyl, etc.), halogen (e.g.,fluoro, chloro, bromo, iodo, etc.), lower alkoxy (e.g., (C₁₋₄)alkoxy,etc.), carboxy, lower alkoxycarbamoyl, carbamoyl, lower alkylcarbamoyl,etc. The number of the substituent may be one or two or more. Where thenumber of the substituent is two or more, the substituents may be thesame or different.

Suitable examples of R¹ may include hydrogen, methylphenyl,(tert-butylamino)sulfonylphenyl, ethylphenyl, methoxyphenyl,aminosulfonylphenyl, etc.

Definition of R²

In the Formula (I), R² is selected from the group consisting ofsubstituted or unsubstituted aryl and substituted or unsubstitutedheteroaryl.

Examples of the “aryl” of the “substituted or unsubstituted aryl” for R²may include aryl similar to those exemplified for R¹ above, in which thepreferred one may be (C₆₋₁₀)aryl, and the more preferred one may bephenyl, etc.

Examples of the substituents for the “substituted aryl” for R² mayinclude halogen (e.g., fluoro, chloro, bromo, iodo, etc.), lower alkyl[e.g., (C₁₋₄)alkyl (e.g., methyl, ethyl, propyl, butyl, etc.), etc.],lower alkoxy [e.g., (C₁₋₄)alkoxy (e.g., methoxy, ethoxy, propoxy,butoxy, etc.), etc.], halo(lower)alkyl (e.g., chloromethyl,dichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl,pentachloroethyl, etc.), hydroxy(lower)alkyl, etc. The number of thesubstituent may be one, two or more. Where the number of the substituentis two or more, the substituents may be the same or different.

Examples of the “heteroaryl” of the “substituted or unsubstitutedheteroaryl” for R² may include, 5 to 14-membered heteroaryl, such asfuryl, pyrrolyl, thienyl, oxazolyl, etc., in which the preferred one maybe 5 or 6-membered heteroaryl, and more preferred one may be thienyl,etc.

Examples of the substituents for the “substituted heteroaryl” for R2 mayinclude substituents similar to the substituents exemplified above forthe “substituted aryl” for R². The number of the substituent may be oneor two or more. Where the number of the substituent is two or more, thesubstituents may be the same or different.

Suitable examples of R² may include phenyl, fluorophenyl,difluorophenyl, chlorofluorophenyl, methylphenyl, dimethylphenyl,methoxyphenyl, methyl(fluoro)phenyl, etc.

Definition of R³

In the Formula (I), R³ is lower alkyl.

Examples of the “lower alkyl” for R³ may include lower alkyl similar tothose exemplified for R¹ above, in which the preferred one may be(C₁₋₄)alkyl.

Suitable examples of R³ may include methyl, ethyl, etc.

Definition of p

In the Formula (I), p is 0, 1 or 2.

Suitable example of p is 0.

Definitions of R⁴ and R⁵

In the Formula (I), R⁴ and R⁵ are each hydrogen or taken together toform a bond.

Definitions of R⁶ and R⁷

In the Formula (I), R⁶ and R⁷ are taken together to form a group of theFormula:

Definition of R⁸

R8 is hydrogen.

Definition of X

X is oxygen or N—R⁹, in which R⁹ is hydrogen, substituted orunsubstituted lower alkanoyl, or substituted or unsubstituted loweralkyl.

Examples of the “lower alkyl” of the “substituted or unsubstituted loweralkyl” for R⁹ may include lower alkyl similar to those exemplified forR¹ above.

Examples of the substituents for the “substituted lower alkyl for R9 mayinclude those exemplified as the substituents for the “substituted loweralkyl” for R¹⁸ and R¹⁹ mentioned below, in which the preferred arecarboxy, hydroxy, (C₁₋₆)alkoxycarbonyl, morpholino, morpholinocarbonylor (C₁₋₆)alkylsulfonyloxy.

Examples of the “lower alkanoyl” of the “substituted or unsubstitutedlower alkanoyl” for R⁹ may include (C₂₋₇)alkanoyl [e.g,(C₁₋₆)alkyl-carbonyl (e.g. acetyl, ethylcarbonyl, propylcarbonyl,butylcarbonyl, pentylcarbonyl, hexylcarbonyl, etc.), etc.].

Examples of the substituents for the “substituted lower alkanoyl” for R⁹may include those exemplified as the substituents for the “substitutedlower alkyl” for R¹⁸ and R¹⁹ mentioned below.

Preferred examples of R⁹ may include hydrogen; (C₁₋₆)alkyl optionallysubstituted by carboxy, hydroxy, (C₁₋₆)alkoxycarbonyl, morpholino,morpholinocarbonyl or (C₁₋₆)alkylsulfonyloxy; (C₂₋₇)alkanoyl, etc.

Alternatively, R⁶ and R⁹ may be taken together to form a bond.

Definitions of m and n

m and n are each 0, 1 or 2.

Definitions of R¹⁰ and R¹¹

In the Formula (IV), R¹⁰ is selected from the group consisting ofhydrogen, halogen, hydroxy, formyl, cyano, substituted or unsubstitutedlower alkyl, substituted or unsubstituted amino, substituted orunsubstituted lower alkoxy, saturated cyclic amino, substituted orunsubstituted carbamoyl, carboxy and substituted or unsubstituted loweralkoxycarbony.

Specifically, R¹⁰ is hydrogen or substituted or unsubstituted loweralkyl.

Examples of the “lower alkyl” for the “substituted or unsubstitutedlower alkyl” for R¹⁰ may include lower alkyl similar to thoseexemplified for R¹ above, in which the preferred one may be (C₁₋₆)alkyland more preferred one may be methyl, ethyl, isopropyl, etc.

Examples of the substituents for the “substituted lower alkyl” for R¹⁰may include:

-   -   (1) hydroxy;    -   (2) arylalkoxy [e.g., (C₆₋₁₄)aryl(C₁₋₆)alkoxy such as benzyloxy,        phenethyloxy, etc.];    -   (3) di(C₆₋₁₄)aryl(C₁₋₆)alkylsilyloxy (e.g.,        methyldiphenylsilyloxy, tert-butyldiphenylsilyloxy, etc.), etc.    -   Preferred examples of R¹⁰ may include hydrogen, (C₁₋₆)alkyl        optionally substituted by (C₆₋₁₄)aryl(C₁₋₆)alkoxy,        di(C₆₋₁₄)aryl(C₁₋₆)alkylsilyloxy or hydroxy, etc.

Examples of the “substituted or unsubstituted amino”, “substituted orunsubstituted lower alkoxy”, “saturated cyclic amino”, “substituted orunsubstituted carbamoyl” and “lower alkoxycarbonyl” for R¹⁰ may besimilar to the “substituted or unsubstituted amino”, “substituted orunsubstituted lower alkoxy”, “saturated cyclic amino”, “substituted orunsubstituted carbamoyl” and “lower alkoxycarbonyl” exemplified above asthe substituents for the “substituted lower alkyl” for R¹² mentionedbelow.

Alternatively, R⁹ and R¹⁰ may be taken together to form lower alkylene(e.g., (C₂₋₆)alkylene such as ethylene, propylene, butylene, pentylene,hexylene, etc.), in which preferred may be propylene, etc.

R¹¹ is selected from the group consisting of hydrogen, halogen,substituted or unsubstituted lower alkyl, carboxy and substituted orunsubstituted lower alkoxycarbonyl.

Examples of the “halogen” for R¹¹ may include chloro, fluoro, bromo,iodo, etc.

Examples of the “lower alkyl” for the “substituted or unsubstitutedlower alkyl” for R¹¹ may include lower alkyl similar to thoseexemplified for R¹ above, and examples of the “lower alkoxycarbonyl” forthe “substituted or unsubstituted lower alkoxycarbonyl” for R¹¹ mayinclude those exemplified above as the substituent (8) for the“substituted lower alkyl” for R¹² mentioned below. Examples of thesubstituents for “substituted lower alkyl” and “substituted loweralkoxycarbonyl” for R¹¹ may include those exemplified as thesubstituents for the “substituted lower alkyl” for R¹.

Specifically, R¹¹ is hydrogen, or lower alkyl.

Examples of the lower alkyl for R¹¹ may include lower alkyl similar tothose exemplified for R¹ above, in which the preferred may be(C₁₋₄)alkyl and more preferred may be methyl, ethyl, isopropyl, etc.

Alternatively, R¹⁰ and R¹¹ may be taken together to form

-   -   (1) substituted or unsubstituted lower alkylene [e.g.,        (C₂₋₆)alkylene (e.g., ethylene, propylene, butylene, pentylene,        hexylene, etc., in which the preferred one may be ethylene,        propylene, butylene, etc.)];    -   (2) substituted or unsubstituted lower alkylidene [e.g.,        (C₁₋₆)alkylidene such as methylidene, ethylidene, propylidene,        butylidene, pentylidene, hexylene, etc., in which the preferred        one may be methylidene, ethylidene, propan-2-ylidene, etc.];    -   (3) oxo, or    -   (4) hydroxyimino, etc.

As used herein, the term “lower alkylene” in the phrase “substitutedlower alkylene” formed by R¹⁰ and R¹¹ may also include alkylene group asdefined above in which one or more carbon atom(s) is (are) replaced byone or more heteroatom(s) selected from a nitrogen atom, an oxygen atomand a sulfur atom, and examples of such lower alkylene formed by R¹⁰ andR¹¹ may include following groups such as, but not limited to,—(CH₂)₂—O(CH₂)₂—, —(CH₂)₂—N—(CH₂)₂—, etc.

Examples of the substituents for the above-mentioned “substituted loweralkylene” formed together by R¹⁰ and R¹¹ may include:

-   -   (1) arylalkoxycarbonyl [e.g., (C₆₋₁₄)aryl(C₁₋₆)alkoxycarbonyl        such as benzyloxycarbonyl, phenetyloxycarbonyl, etc.];    -   (2) acyl [e.g., (C₁₋₇)alkanoyl such as formyl, acetyl,        propionyl, butyryl, etc., (C₆₋₁₄)acyl such as benzoyl, etc.],        etc.

Preferred examples of the “substituted or unsubstituted lower alkylene”formed by R¹⁰ and R¹¹ may include (C₂₋₆)alkylene in which one or morecarbon atom(s) may be replaced with heteroatom(s) selected from anoxygen atom and a nitrogen atom, which is optionally substituted by(C₆₋₁₄)aryl(C₁₋₆)alkoxycarbonyl or (C₁₋₇)alkanoyl.

Alternatively, R⁹ and R¹⁰ may be taken together to form lower alkyleneor a bond.

Examples of the “lower alkylene” formed by R⁹ and R^(n) may include(C₂₋₆)alkylene, in which preferred are propylene, etc.

Definitions of R¹², R¹³ and R¹⁴

In the above-mentioned Formula (I), R¹² is selected from the groupconsisting of hydrogen, halogen, hydroxy, formyl, cyano, substituted orunsubstituted lower alkyl, substituted or unsubstituted amino,substituted or unsubstituted lower alkoxy, saturated cyclic amino,substituted or unsubstituted carbamoyl, carboxy and substituted orunsubstituted lower alkoxycarbonyl, substituted or unsubstitutedacyloxy.

Examples of the “halogen” for R¹² may include chloro, fluoro, bromo,iodo, etc., in which the preferred one may be fluoro, etc.

Examples of the “lower alkyl” of the “substituted or unsubstituted loweralkyl” for R¹² may include lower alkyl similar to those exemplifiedabove for R¹, in which the preferred one may be (C₁₋₄)alkyl and morepreferred one may be methyl, ethyl, isopropyl, etc.

Examples of the substituents for the “substituted lower alkyl” for R¹²may include:

-   -   (1) hydroxy, hydroxyimino or tri(lower)alkylsilyloxy;    -   (2) halogen (e.g., chloro, fluoro, bromo, iodo, etc.);    -   (3) substituted or unsubstituted amino [e.g., amino, mono- or        di-(substituted or unsubstituted lower alkyl)amino (e.g.,        mono-(C₁₋₆)alkylamino in which said (C₁₋₆)alkyl may be        substituted by (C₆₋₁₄)aryl, (C₃₋₈)cycloalkylcarbonyl or hydroxy        (e.g., methylamino, ethylamino, propyl amino, isopropylamino,        butylamino, tert-butylamino, neopentylamino, hydroxymethylamino,        hydroxyethylamino, cyclopropanecarbonylamino, etc.),        di-(C₁₋₄)alkylamino in which one or both of said (C₁₋₄)alkyl may        be substituted by (C₆₋₁₄)aryl (e.g., dimethylamino,        diethylamino, ethylmethylamino, etc.), 2-hydroxyethylamino,        2-methoxyethylamino, 2-(dimethylamino)ethylamino,        2-hydroxy-1,1-dimethylethylamino,        2-hydroxy-1-(hydroxymethyl)ethylamino,        (2-hydroxyethyl)methylamino, (2-methoxyethyl)methylamino,        benzylmethylamino, tert-butylbenzylamino, dibenzylamino etc.),        mono-(C₂₋₇) alkanoylamino (e.g., acetylamino,        ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino,        butylcarbonylamino, pentylcarbonylamino, hexylcarbonylamino,        etc.), (C₃₋₈)cycloalkylamino (e.g., cyclopropylamino,        cyclobutylamino, cyclopentylamino, cyclohexylamino, etc.),        etc.];    -   (4) substituted or unsubstituted lower alkoxy (e.g.,        (C₁₋₆)alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,        butoxy, neopentyloxy, etc.), (C₆₋₁₄)aryl(C₁₋₆)alkoxy (e.g.,        benzyloxy, etc.), 2-hydroxyethyloxy,        2-hydroxy-1,1-dimethylethyloxy, 2-methoxyethyloxy,        2-(dimethylamino)ethyloxy, etc.);    -   (5) saturated cyclic amino [e.g., 4-, 5- or 6-membered saturated        cyclic amino which may further have heteroatom(s) selected from        a nitrogen atom, an oxygen atom and a sulfur atom and/or oxo        besides the amino nitrogen and may have substituent(s), such as        azetidinyl (e.g., 3-hydroxy-1-azetidinyl, 3-amino-1-azetidinyl,        3-methylamino-1-azetidinyl, etc.), pyrrolidinyl (e.g.,        1-pyrrolidinyl, 3-hydroxy-1-pyrrolidinyl,        3-amino-1-pyrrolidinyl, 3-methylamino-1-pyrrolidinyl, etc.),        morpholinyl (e.g., morpholino, etc.),        4-(lower)alkyl-1-piperazinyl (e.g., 4-methyl-1-piperazinyl,        4-isopropyl-1-piperazinyl, etc.), 4-(mono- or        di-(lower)alkylamino)-1-piperidinyl (e.g.,        4-(dimethylamino)-1-piperidinyl, etc.), oxopyrrolidinyl (e.g.,        2-oxo-1-pyrrolidinyl, etc.), etc.];    -   (6) substituted or unsubstituted carbamoyl [e.g., carbamoyl,        (lower)alkylcarbamoyl (e.g., (C₁₋₄)alkylcarbamoyl such as        methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl,        isopropylcarbamoyl, butylcarbamoyl, etc.),        (C₃₋₈)cycloalkylcarbamoyl (e.g., cyclopropylcarbamoyl, etc.),        etc.];    -   (7) carboxy;    -   (8) lower alkoxycarbonyl [e.g., (C₁₋₆)alkoxycarbonyl (e.g.,        methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl,        tert-butoxycarbonyl, pentyloxycarbamoyl, hexyloxycarbamoyl,        etc.), etc.];    -   (9) lower alkylureido [e.g., (C₁₋₆)alkylureido (e.g.,        methylureido, ethylureido, etc.)]    -   (10) lower acyloxy [e.g., (C₁₋₇)alkanoyloxy (e.g., formyloxy,        acetyloxy, ethylcarbonyloxy, propylcarbonyloxy,        butylcarbonyloxy, pentylcarbonyloxy, hexylcarbonyloxy, etc.],        etc.

The number of the substituent may be one, two or more. Where the numberof the substituent is two or more, the substituents may be the same ordifferent.

Examples of the “substituted or unsubstituted amino”, “saturated cyclicamino”, “substituted or unsubstituted lower alkoxy”, “substituted orunsubstituted carbamoyl” and “lower alkoxycarbonyl” for R¹² may besimilar to the “substituted or unsubstituted amino”, “saturated cyclicamino”, “substituted or unsubstituted lower alkoxy”, “substituted orunsubstituted carbamoyl” and “substituted or unsubstituted loweralkoxycarbonyl” exemplified above as the substituents of the“substituted lower alkyl” for R¹².

Examples of the “acyloxy” for the “substituted or unsubstituted acyloxy”for R¹² may include lower acyloxy similar to those exemplified above asthe substituent (10) for the “substituted lower alkyl” for R¹² mentionedabove.

Examples of the substituents for the “substituted acyloxy” for R¹² maybe similar to those exemplified as the substituents for the “substitutedlower alkyl” for R¹².

Preferable examples for R¹² may include hydrogen; halogen; hydroxy;carboxy; formyl; cyano; hydroxycyano; (C₁₋₆)alkyl optionally substitutedby hydroxy, hydroxyimino, halogen, (C₁₋₆)alkoxy, (C₁₋₇)alkanoyloxy,amino, mono- or di-(C₁₋₆)alkylamino (in which one or both of said(C₁₋₆)alkyl is (are) optionally substituted by hydroxy, (C₁₋₆)alkoxy,(C₆₋₁₄)aryl or (C₃₋₆)cycloalkyl-carbonyl), (C₁₋₆)alkylureido,morpholino, (C₁₋₇)alkanoyloxy, or 4- to 6-membered cyclic aminooptionally substituted by hydroxy, (C₁₋₆)alkyl or di(C₁₋₆)alkylamino;mono- or di-(C₁₋₇)alkylamino; 4- to 6-membered cyclic amino;(C₁₋₆)alkoxy optionally substituted by (C₆₋₁₄)aryl; carbamoyl optionallysubstituted by (C₃₋₆)cycloalkyl or hydroxy(C₁₋₆)alkyl;(C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkoxycarbonyloxy, etc.

Among the above-mentioned substituents, suitable examples of R¹² mayinclude hydrogen, fluoro, hydroxy, formyl, cyano, methyl, aminomethyl,tert-butylaminomethyl, dimethylaminomethyl, diethylaminomethyl,dibenzylaminomethyl, benzylmethylaminomethyl,benzyl(tert-buthyl)aminomethyl, methoxycarbonylmethyl,3-hydroxyazetinylmethyl, 4-methylpiperazinylmethyl, pyrrolidinylmethyl,hydroxymethyl, hydroxyethylaminomethyl, methoxyethylaminomethyl,iodomethyl, methylaminomethyl, morpholinomethyl,(2-hydroxyethyl)methylaminomethyl, acetyloxymethyl,4-(dimethylamino)-1-piperidinylmethyl, ethoxycarbonylmethyl,cyclopropylcarbamoylmethyl, ethylureidomethyl, hydroxyiminomethyl,dimethylamino, isopropylamino, 3-hydroxy-1-azetidinyl, piperidino,morpholino, benzyloxy, neopentyloxy, carboxy, methoxycarbonyl,ethoxycarbonyl, tert-butoxycarbonyl, carbamoyl, cyclopropylcarbamoyl,etc.

R¹³ is selected from the group consisting of hydrogen, halogen,substituted or unsubstituted lower alkyl, carboxy and substituted orunsubstituted lower alkoxycarbonyl.

Examples of the “halogen” and “substituted or unsubstituted loweralkoxycarbonyl” for R¹³ may be similar to those exemplified for R¹¹.

Examples of the “lower alkyl” of the “substituted or unsubstituted loweralkyl” for R¹³ may include lower alkyl similar to those exemplifiedabove for R¹, in which the preferred one may be (C₁₋₄)alkyl, and morepreferred one may be methyl, ethyl, isopropyl, etc.

Examples of the substituents for the “substituted lower alkyl” for R¹³may include

-   -   (1) hydroxy;    -   (2) halogen (e.g., chloro, fluoro, bromo, iodo, etc.);    -   (3) substituted or unsubstituted amino [e.g., amino, mono- or        di-(substituted or unsubstituted lower alkyl)amino (e.g.,        mono-(C₁₋₆)alkylamino (e.g., methylamino, ethylamino,        propylamino, isopropylamino, butylamino, tert-butylamino,        neopentylamino, etc.), di-(C₁₋₄)alkylamino (e.g., dimethylamino,        diethylamino, ethylmethylamino, etc.), 2-hydroxyethylamino,        2-methoxyethylamino, 2-(dimethylamino)ethylamino,        2-hydroxy-1,1-dimethylethylamino,        2-hydroxy-1-(hydroxymethyl)ethylamino,        (2-hydroxyethyl)methylamino, (2-methoxyethyl)methylamino, etc.),        mono-(C₂₋₇)alkanoylamino (e.g., acetylamino, ethylcarbonylamino,        propylcarbonylamino, isopropylcarbonylamino, butylcarbonylamino,        pentylcarbonylamino, hexylcarbonylamino, etc.),        (C₃₋₈)cycloalkylamino (e.g., cyclopropylamino, cyclobutylamino,        cyclopentylamino, cyclohexylamino, etc.), etc.];    -   (4) substituted or unsubstituted lower alkoxy [e.g.,        (C₁₋₄)alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,        butoxy, etc.), 2-hydroxyethyloxy,        2-hydroxy-1,1-dimethylethyloxy, 2-methoxyethyloxy,        2-(dimethylamino)ethyloxy, etc.];    -   (5) lower alkanoyloxy [e.g., (C₁₋₇)alkanoyloxy [e.g., formyloxy,        acetyloxy, ethylcarbonyloxy, propylcarbonyloxy,        butylcarbonyloxy, pentylcarbonyloxy, hexylcarbonyloxy, etc.];        etc.    -   The number of the substituent may be one, two or more. Where the        number of the substituent is two or more, the substituents may        be the same or different.

Suitable examples of R¹³ may include hydrogen, halogen (e.g., fluoro,etc.), (C₁₋₆)alkyl optionally substituted by hydroxy, fluoro, halogen,(C₁₋₆)alkoxy or (C₁₋₇)alkanoyl (e.g., methyl, hydroxymethyl,fluoromethyl, methoxymethyl, acetyloxymethyl, etc.), in which preferredare hydrogen, halogen or (C₁₋₆)alkyl optionally substituted by hydroxyor (C₁₋₇)alkanoyloxy (e.g., hydroxymethyl, acetyloxymethyl, etc.), etc.

R¹⁴ is selected from the group consisting of hydrogen, halogen,substituted or unsubstituted lower alkyl, carboxy and substituted orunsubstituted lower alkoxycarbonyl.

The “halogen”, “substituted or unsubstituted lower alkyl” and“substituted or unsubstituted lower alkoxycarbonyl” for R¹⁴ may besimilar to those exemplified for R¹¹.

Preferably, R14 is hydrogen.

Alternatively, R¹² and R¹³ may be taken together to form (1) substitutedor unsubstituted lower alkylene [e.g., (C₂₋₆)alkylene (e.g., ethylene,propylene, butylene, pentylene, hexylene, etc., in which the preferredone may be ethylene, propylene, butylene, etc.)];

-   -   (2) substituted or unsubstituted lower alkylidene (e.g.,        (C₁₋₆)alkylidene such as methylidene, ethylidene, propylidene,        butylidene, pentylidene, hexylidene, etc., in which the        preferred one may be methylidene, ethylidene, propan-2-ylidene,        etc.];    -   (3) oxo, or    -   (4) hydroxyimino.

The term “lower alkylene” in the phrase “substituted or unsubstitutedlower alkylene” for R¹² and R¹³ refers to alkylene group as definedabove in which one or more carbon atom(s) is (are) replaced by one ormore heteroatom(s) selected from a nitrogen atom, an oxygen atom and asulfur atom

Examples of the substituents for the above-mentioned “substituted loweralkylene” formed by R¹² and R¹³ may include

-   -   (1) substituents for “substituted or unsubstituted lower alkyl”        for R¹²; and    -   (2) substituted or unsubstituted lower alkyl [e.g., substituted        or unsubstituted (C₁₋₆)alkyl (e.g., methyl, ethyl, propyl,        isopropyl, n-butyl, tert-butyl, pentyl, hexyl, etc.), examples        of the substituent may include the substituents for the        “substituted or unsubstituted lower alkyl” for R¹²]

Suitable examples of the “substituted or unsubstituted lower alkylene”formed by R¹² and R¹³ may include following groups such as, but notlimited to:

Examples of the substituents for the above-mentioned “substituted loweralkylidene” formed by R¹² and R¹³ may be similar to those exemplifiedfor the “substituted or unsubstituted alkylene” formed by R¹² and R¹³.

Suitable examples of the “substituted or unsubstituted lower alkylidene”formed by R¹² and R¹³ may include (C₁₋₆)alkylidene optionallysubstituted by hydroxy, such as the following groups, but not limitedto, —CH₂═CH—CH₃═CH—CH₂—OH, etc.

Alternatively, R¹¹ and R¹² or R¹³ and R¹⁴ may be taken together to forma bond.

In an embodiment of the present invention, R⁶ and R⁷ are taken togetherto form the following structure (A), (B1) or (B2).

Definition of R¹⁵

In the above-mentioned Formula (A), R¹⁵ is selected from the groupconsisting of hydroxy, substituted or unsubstituted lower alkyl,substituted or unsubstituted amino, substituted or unsubstituted loweralkoxy, saturated cyclic amino, lower substituted or unsubstitutedcarbamoyl, carboxy and substituted or unsubstituted loweralkoxycarbonyl.

Examples of the “lower alkyl” of the “substituted or unsubstituted loweralkyl” for R¹⁵ may include lower alkyl similar to those exemplified forR¹ above, in which the preferred one may be (C₁₋₄)alkyl and morepreferred one may be methyl, ethyl, isopropyl, etc.

Examples of the substituents for the “substituted lower alkyl” for R¹⁵may include:

-   -   (1) hydroxy;    -   (2) substituted or unsubstituted amino [e.g., amino, mono or        di-(substituted or unsubstituted lower alkyl)amino (e.g.,        mono-(C₁₋₆)alkylamino such as methylamino, ethylamino,        propylamino, isopropylamino, butylamino, tert-butylamino,        neopentylamino, etc.; di-(C₁₋₄)alkylamino such as dimethylamino,        diethylamino, ethylmethylamino, etc.; 2-hydroxyethylamino,        2-methoxyethylamino, 2-(dimethylamino)ethylamino,        2-hydroxy-1,1-dimethylethylamino,        2-hydroxy-1-(hydroxymethyl)ethylamino,        (2-hydroxyethyl)methylamino, (2-methoxyethyl)methylamino, etc.),        mono-(C₂₋₅)alkanoylamino (e.g., acetylamino, ethylcarbonylamino,        propylcarbonylamino, isopropylcarbonylamino, butylcarbonylamino,        etc.), (C₃₋₆)cycloalkylamino (e.g., cyclopropylamino,        cyclobutylamino, cyclopentylamino, cyclohexylamino, etc.),        etc.);    -   (3) substituted or unsubstituted lower alkoxy [e.g.,        (C₁₋₄)alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,        butoxy, etc.), 2-hydroxyethyloxy,        2-hydroxy-1,1-dimethylethyloxy, 2-methoxyethyloxy,        2-(dimethylamino)ethyloxy, etc.];    -   (4) saturated cyclic amino [e.g., 4-, 5- or 6-membered saturated        cyclic amino which may further have heteroatom(s) selected from        a nitrogen atom, an oxygen atom and a sulfur atom and/or oxo        besides the amino nitrogen and may have substituent(s), such as        azetidinyl (e.g., 3-hydroxy-1-azetidinyl, 3-amino-1-azetidinyl),        pyrrolidinyl (e.g., 1-pyrrolidinyl, etc.), morpholinyl (e.g.,        morpholino, etc.), 4-(lower)alkyl-1-piperazinyl (e.g.,        4-methyl-1-piperazinyl, 4-isopropyl-1-piperazinyl, etc.),        oxopyrrolidinyl (e.g., 2-oxo-1-pyrrolidinyl, etc.), etc.];    -   (5) substituted or unsubstituted carbamoyl [e.g., carbamoyl,        (lower)alkylcarbamoyl (e.g., (C₁₋₄)alkylcarbamoyl such as        methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl,        isopropylcarbamoyl, butylcarbamoyl, etc.), etc.],    -   (6) carboxy;    -   (7) lower alkoxycarbonyl [e.g., (C₁₋₆)alkoxycarbonyl (e.g.,        methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl,        pentyloxycarbonyl, hexyloxycarbonyl), etc.], etc. The number of        the substituent may be one, two or more. Where the number of the        substituent is two or more, the substituents may be the same or        different.

Examples of the “substituted or unsubstituted amino”, “substituted orunsubstituted lower alkoxy”, “saturated cyclic amino”, “substituted orunsubstituted carbamoyl” and “lower alkoxycarbonyl” for R¹⁵ may besimilar to the “substituted or unsubstituted amino”, “substituted orunsubstituted lower alkoxy”, “saturated cyclic amino”, “substituted orunsubstituted carbamoyl” and “lower alkoxycarbonyl” exemplified above asthe substituents for the “substituted lower alkyl” for R¹⁵.

Suitable examples of R¹⁵ may include dimethylaminomethyl,methylaminomethyl, hydroxymethyl, morpholino, 3-hydroxyl-azetidinyl,etc.

Definitions of R⁶ and R¹⁷

In the above-mentioned Formula (B1), R¹⁶ is selected from the groupconsisting of hydrogen, halogen, hydroxy, substituted or unsubstitutedlower alkyl, substituted or unsubstituted amino, saturated cyclic amino,substituted or unsubstituted lower alkoxy, substituted or unsubstitutedcarbamoyl, carboxy and lower alkoxycarbonyl.

Examples of the “halogen” for R¹⁶ may include chloro, fluoro, bromo,iodo, etc., in which the preferred one may be fluoro, etc.

Examples of the “lower alkyl” of the “substituted or unsubstituted loweralkyl” for R¹⁶ may include lower alkyl similar to those exemplified forR¹ above, in which the preferred one may be (C₁₋₄)alkyl and morepreferred one may be methyl, ethyl, isopropyl, etc.

Examples of the substituents for the “substituted lower alkyl” for R¹⁶may include:

-   -   (1) hydroxy or tri(lower)alkylsilyloxy;    -   (2) halogen (e.g., chloro, fluoro, bromo, iodo, etc.);    -   (3) substituted or unsubstituted amino [e.g., amino, mono- or        di-(substituted or unsubstituted lower alkyl)amino (e.g.,        mono-(C₁₋₆)alkylamino (e.g., methylamino, ethylamino,        propylamino, isopropylamino, butylamino, tert-butylamino,        neopentylamino, etc.), di-(C₁₋₄)alkylamino (e.g., dimethylamino,        diethylamino, ethylmethylamino, etc.), 2-hydroxyethylamino,        2-methoxyethylamino, 2-(dimethylamino)ethylamino,        2-hydroxy-1,1-dimethylethylamino,        2-hydroxy-1-(hydroxymethyl)ethylamino,        (2-hydroxyethyl)methylamino, (2-methoxyethyl)methylamino, etc.),        mono-(C₂-5)alkanoylamino (e.g., acetylamino, ethylcarbonylamino,        propylcarbonylamino, isopropylcarbonylamino, butylcarbonylamino,        etc.), (C₃₋₈) cycloalkylamino (e.g., cyclopropylamino,        cyclobutylamino, cyclopentylamino, cyclohexylamino, etc.),        etc.];    -   (4) substituted or unsubstituted lower alkoxy (e.g.,        (C₁₋₄)alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,        butoxy, etc.), 2-hydroxyethyloxy,        2-hydroxy-1,1-dimethylethyloxy, 2-methoxyethyloxy,        2-(dimethylamino)ethyloxy, etc.);    -   (5) saturated cyclic amino [e.g., 4-, 5- or 6-membered saturated        cyclic amino which may further have heteroatom(s) selected from        a nitrogen atom, an oxygen atom and a sulfur atom and/or oxo        besides the amino nitrogen and may have substituent(s), such as        azetidinyl (e.g., 3-hydroxy-1-azetidinyl, 3-amino-1-azetidinyl,        3-methylamino-1-azetidinyl, etc.), pyrrolidinyl (e.g.,        1-pyrrolidinyl, 3-hydroxy-1-pyrrolidinyl,        3-amino-1-pyrrolidinyl, 3-methylamino-1-pyrrolidinyl, etc.),        morpholinyl (e.g., morpholino, etc.),        4-(lower)alkyl-1-piperazinyl (e.g., 4-methyl-1-piperazinyl,        4-isopropyl-1-piperazinyl, etc.), 4-(mono- or        di-(lower)alkylamino)-1-piperidinyl (e.g.,        4-(dimethylamino)-1-piperidinyl, etc.), oxopyrrolidinyl (e.g.,        2-oxo-1-pyrrolidinyl, etc.), etc.];    -   (6) substituted or unsubstituted carbamoyl [e.g., carbamoyl,        (lower)alkylcarbamoyl (e.g., (C₁₋₄)alkylcarbamoyl such as        methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl,        isopropylcarbamoyl, butylcarbamoyl, etc.), etc.];    -   (7) carboxy;    -   (8) lower alkoxycarbonyl [e.g., (C₁₋₄)alkoxycarbonyl (e.g.,        methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.),        etc.], etc. The number of the substituent may be one or two or        more. Where the number of the substituent is two or more, the        substituents may be the same or different.

Examples of the “substituted or unsubstituted amino”, “saturated cyclicamino”, “substituted or unsubstituted lower alkoxy”, “substituted orunsubstituted carbamoyl” and “lower alkoxycarbonyl” for R¹⁶ may besimilar to the “substituted or unsubstituted amino”, “saturated cyclicamino”, “substituted or unsubstituted lower alkoxy”, “substituted orunsubstituted carbamoyl” and “lower alkoxycarbonyl” exemplified as thesubstituents of the “substituted or unsubstituted lower alkyl” for R⁷.

Suitable examples of R¹⁶ may include hydrogen, fluoro, hydroxy,dimethylaminomethyl, hydroxymethyl, iodomethyl,4-(dimethylamino)-1-piperidinylmethyl, dimethylamino, piperidino,isopropylamino, methylaminomethyl, morpholinomethyl,(2-hydroxyethyl)methylaminomethyl, morpholino, carboxy, methoxycarbonyl,tert-butoxycarbonyl, 3-hydroxy-1-azetidinyl, etc.

In the above-mentioned Formula (B1), R¹⁷ is selected from the groupconsisting of hydrogen, halogen, substituted or unsubstituted loweralkyl, carboxy and lower alkoxycarbonyl.

Examples of the “halogen” for R¹⁷ may include chloro, fluoro, bromo,iodo, etc., in which the preferred one may be fluoro, etc.

Examples of the “lower alkyl” of the “substituted or unsubstituted loweralkyl” for R¹⁷ may include lower alkyl similar to those exemplified forR¹ above, in which the preferred one may be (C₁₋₄)alkyl, and morepreferred one may be methyl, ethyl, isopropyl, etc.

Examples of the substituents for the “lower alkyl” for R¹⁷ may include

-   -   (1) hydroxy;    -   (2) halogen (e.g., chloro, fluoro, bromo, iodo, etc.);    -   (3) substituted or unsubstituted amino [e.g., amino, mono- or        di-(substituted or unsubstituted lower alkyl)amino (e.g.,        mono-(C₁₋₆)alkylamino (e.g., methylamino, ethylamino,        propylamino, isopropylamino, butylamino, t-butylamino,        neopentylamino, etc.), di-(C₁₋₄)alkylamino (e.g., dimethylamino,        diethylamino, ethylmethylamino, etc.), 2-hydroxyethylamino,        2-methoxyethylamino, 2-(dimethylamino)ethylamino,        2-hydroxy-1,1-dimethylethylamino,        2-hydroxy-1-(hydroxymethyl)ethylamino,        (2-hydroxyethyl)methylamino, (2-methoxyethyl)methylamino, etc.),        mono-(C₂₋₅)alkanoylamino (e.g., acetylamino, ethylcarbonylamino,        propylcarbonylamino, isopropylcarbonylamino, butylcarbonylamino,        etc.), (C₃₋₈) cycloalkylamino (e.g., cyclopropylamino,        cyclobutylamino, cyclopentylamino, cyclohexylamino, etc.),        etc.];    -   (4) substituted or unsubstituted lower alkoxy [e.g.,        (C₁₋₄)alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,        butoxy, etc.), 2-hydroxyethyloxy,        2-hydroxy-1,1-dimethylethyloxy, 2-methoxyethyloxy,        2-(dimethylamino)ethyloxy, etc.], etc. The number of the        substituent may be one or two or more. Where the number of the        substituent is two or more, the substituents may be the same or        different.

Suitable examples of R¹⁷ may include hydrogen, methyl, hydroxymethyl,fluoro, fluoromethyl, methoxymethyl, etc.

Alternatively, R¹⁶ and R¹⁷ are taken together to form lower alkylene orlower alkylidene.

Examples of the “lower alkylene” for R¹⁶ and R¹⁷ may include(C₂₋₆)alkylene such as ethylene, propylene, butylene, pentylene,hexylene, etc., in which the preferred one may be ethylene, propylene,butylene, etc.

Examples of the “lower alkylidene” for R¹⁶ and R¹⁷ may include(C₁₋₆)alkylidene such as methylidene, ethylidene, propylidene,butylidene, pentylidene, hexylene, etc., in which the preferred one maybe methylidene, ethylidene, propan-2-ylidene, etc.

Definition of R¹⁸

In the above-mentioned Formula (B1), R¹⁸ is hydrogen or substituted orunsubstituted lower alkyl; provided that when both R¹⁶ and R¹⁷ aresimultaneously hydrogen, R¹ is substituted or unsubstituted lower alkyl.

Examples of the “lower alkyl” of the “substituted or unsubstituted loweralkyl” for R18 may include lower alkyl similar to those exemplified forR¹ above, in which the preferred one may be (C₁₋₄)alkyl and morepreferred one may be ethyl, propyl, etc.

Examples of the substituents for the “substituted lower alkyl” for R¹⁸may include

-   -   (1) hydroxy;    -   (2) carboxy;    -   (3) halogen (chloro, fluoro, bromo, iodo);    -   (4) (lower)alkoxycarbonyl [e.g., (C₁₋₆)alkoxycarbonyl (e.g.,        methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,        butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl,        hexyloxycarbonyl, etc.), etc.];    -   (5) substituted or unsubstituted amino (e.g., amino, mono- or        di-(substituted or unsubstituted lower alkyl)amino (e.g.,        mono-(C₁₋₆)alkylamino (e.g., methylamino, ethylamino,        propylamino, isopropylamino, butylamino, tert-butylamino,        neopentylamino, etc.), di-(C₁₋₄)alkylamino (e.g., dimethylamino,        diethylamino, ethylmethylamino, etc.), 2-hydroxyethylamino,        2-methoxyethylamino, 2-(dimethylamino)ethylamino,        2-hydroxy-1,1-dimethyl ethyl amino,        2-hydroxy-1-(hydroxymethyl)ethyl amino,        (2-hydroxyethyl)methylamino, (2-methoxyethyl)methylamino, etc.),        mono-(C₂₋₅)alkanoylamino (e.g., acetylamino, ethylcarbonylamino,        propylcarbonylamino, isopropylcarbonylamino, butylcarbonylamino,        etc.), (C₃₋₉)cycloalkylamino (e.g., cyclopropylamino,        cyclobutylamino, cyclopentylamino, cyclohexylamino, etc.),        etc.];    -   (6) substituted or unsubstituted lower alkoxy [e.g.,        (C₁₋₄)alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,        butoxy, etc.), 2-hydroxyethyloxy,        2-hydroxy-1,1-dimethylethyloxy, 2-methoxyethyloxy,        2-(dimethylamino)ethyloxy, etc.];    -   (7) saturated cyclic amino [e.g., 4, 5- or 6-membered saturated        cyclic amino which may further have heteroatom(s) selected from        a nitrogen atom, an oxygen atom and a sulfur atom and/or oxo        besides the amino nitrogen and may have substituent(s), such as        azetidinyl (e.g., 3-hydroxy-1-azetidinyl, 3-amino-1-azetidinyl,        3-methylamino-1-azetidinyl, etc.), pyrrolidinyl (e.g.,        1-pyrrolidinyl, 3-hydroxy-1-pyrrolidinyl,        3-amino-1-pyrrolidinyl, 3-methylamino-1-pyrrolidinyl, etc.),        morpholinyl (e.g., morpholino, etc.),        4-(lower)alkyl-1-piperazinyl (e.g., 4-methyl-1-piperazinyl,        4-isopropyl-1-piperazinyl, etc.), 4-(mono- or        di-(lower)alkylamino)-1-piperidinyl (e.g.,        4-(dimethylamino)-1-piperidinyl, etc.), oxopyrrolidinyl (e.g.,        2-oxo-1-pyrrolidinyl, etc.), etc.];    -   (8) lower alkylsulfonyloxy [e.g., (C₁₋₆)alkylsulfonyloxy (e.g.,        methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy,        butylsulfonyloxy, pentylsulfonyloxy, hexylsulfonyloxy, etc.),        etc.];    -   (9) substituted or unsubstituted arylsulfonyloxy (e.g.,        p-toluenesulfonyloxy, benzenesulfonyloxy, mesitylenesulfonyloxy,        etc.), etc. The number of the substituent may be one or two or        more. Where the number of the substituent is two or more, the        substituents may be the same or different.

Suitable examples of R¹⁸ may include hydrogen, methyl, ethyl,tert-butoxycarbonylethyl, carboxyethyl, hydroxypropyl, methoxyethyl,hydroxyethyl, dimethylaminopropyl, etc.

Definition of R¹⁹

In the above-mentioned Formula (B2), R¹⁹ is hydrogen or substituted orunsubstituted lower alkyl.

Examples of the “lower alkyl” of the “substituted or unsubstituted loweralkyl” for R19 may include lower alkyl similar to those exemplified forR¹ above, in which the preferred one may be (C₁₋₁₄)alkyl and morepreferred one may be ethyl, propyl, etc.

Examples of the substituents for the “substituted lower alkyl” for R¹⁹may include

-   -   (1) hydroxy;    -   (2) carboxy;    -   (3) (lower)alkoxycarbonyl [e.g., (C₁₋₆)alkoxycarbonyl (e.g.,        methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,        butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.),        etc.];    -   (4) saturated cyclic amino [e.g., 4-, 5- or 6-membered saturated        cyclic amino which may further have heteroatom(s) selected from        a nitrogen atom, an oxygen atom and a sulfur atom and/or oxo        besides the amino nitrogen and may have substituent(s), such as        azetidinyl (e.g., 3-hydroxy-1-azetidinyl, 3-amino-1-azetidinyl,        etc.), morpholinyl (e.g., morpholino, etc.), etc.];    -   (5) (saturated cyclic amino)carbonyl [e.g., a group in which the        saturated cyclic amino as exemplified in (4) above is attached        to a carbonyl group (e.g., morpholinocarbonyl, etc.), etc.];    -   (6) (lower)alkylsulfonyloxy [e.g., (C₁₋₆)alkylsulfonyloxy (e.g.,        methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy,        butylsulfonyloxy, pentylcarbonyloxy, hexylcarbonyloxy, etc.),        etc.];    -   (7) substituted or unsubstituted amino [e.g., amino, mono- or        di-(substituted or unsubstituted lower alkyl)amino (e.g.,        mono-(C₁₋₆)alkylamino (e.g., methylamino, ethylamino,        propylamino, isopropylamino, butylamino, tert-butylamino,        neopentylamino, etc.), di-(C₁₋₄)alkylamino (e.g., dimethylamino,        diethylamino, ethylmethylamino, etc.), 2-hydroxyethylamino,        2-methoxyethylamino, 2-(dimethylamino)ethylamino,        2-hydroxy-1,1-dimethyl ethyl amino,        2-hydroxy-1-(hydroxymethyl)ethyl amino,        (2-hydroxyethyl)methylamino, (2-methoxyethyl)methylamino, etc.),        mono-(C₂-5)alkanoylamino (e.g., acetylamino, ethylcarbonylamino,        propylcarbonylamino, isopropylcarbonylamino, butylcarbonylamino,        etc.), (C₃₋₈) cycloalkylamino (e.g., cyclopropylamino,        cyclobutylamino, cyclopentylamino, cyclohexylamino, etc.),        etc.),    -   (8) substituted or unsubstituted arylsulfonyloxy (e.g.,        p-toluenesulfonyloxy, benzenesulfonyloxy, mesitylenesulfonyloxy,        etc.);    -   (9) halogen (e.g., chloro, fluoro, bromo, iodo, etc.), etc. The        number of the substituent may be one or two or more. Where the        number of the substituent is two or more, the substituents may        be the same or different.

Suitable examples of R¹⁹ may include methyl, ethyl, propyl,methoxyethyl, methoxypropyl, hydroxyethyl, ethoxycarbonylethyl,carboxyethyl, hydroxypropyl, morpholinocarbonylethyl, methylsulfonyloxypropyl, morpholinopropyl, methylaminopropyl,dimethylaminopropyl, etc.

Genus V Description

Compounds of Genus V can be prepared according to the disclosure of U.S.Pat. No. 7,125,898, which is herein incorporated herein by reference inits entirety.

Genus V is characterized by compounds of Formula V:

or stereoisomers thereof, isotopically-enriched compounds thereof,prodrugs thereof, solvates thereof, and pharmaceutically acceptablesalts thereof;wherein:

-   R¹ is selected from hydrogen, C₁₋₆alkyl optionally substituted by up    to three groups selected from C₁₋₆alkoxy, halogen and hydroxy,    C₂₋₆alkenyl, C₃₋₇cycloalkyl optionally substituted by one or more    C₁₋₆alkyl groups, phenyl optionally substituted by up to three    groups selected from R⁵ and R⁶, and heteroaryl optionally    substituted by up to three groups selected from R⁵ and R⁶,-   R² is selected from hydrogen, C₁₋₆alkyl and    —(CH₂)_(q)—C₃₋₇cycloalkyl optionally substituted by one or more    C₁₋₆alkyl groups, or    -   —(CH₂)_(m)R¹ and R² taken together with the nitrogen atom to        which they are bound, form a 4-6-membered heterocyclic ring        optionally substituted by up to three C₁₋₆alkyl groups;-   R³ is chloro or methyl;-   R⁴ is —NH—CO—R⁷ or —CO—NH(CH₂)_(q)—R⁸;-   R⁵ is selected from C₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(q)—C₃₋₇cycloalkyl    optionally substituted by one or more C₁₋₆alkyl groups, —CONR⁹R¹⁰,    —NHCOR¹⁰, —SO₂NHR⁹, (CH₂)_(S)NHSO₂R¹⁰, halogen, —CN, —OH,    —(CH₂)_(S)NR¹¹R¹², and trifluoromethyl;-   R⁶ is selected from C₁₋₆alkyl, C₁₋₆alkoxy, halogen, trifluoromethyl,    and —(CH₂)_(S)NR¹¹R¹²;-   R⁷ is selected from hydrogen, C₁₋₆alkyl, —(CH₂)_(q)—C₃₋₇cycloalkyl    optionally substituted by one or more C₁₋₆alkyl groups,    trifluoromethyl, —(CH₂)_(r)-heteroaryl optionally substituted by R¹³    and/or R¹⁴, and —(CH₂)_(r)-phenyl optionally substituted by R¹³    and/or R¹⁴;-   R⁸ is selected from hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl optionally    substituted by one or more C₁₋₆alkyl groups, —CONHR⁹, phenyl    optionally substituted by R¹³ and/or R¹⁴, and heteroaryl optionally    substituted by R¹³ and/or R¹⁴;-   R⁹ and R¹⁰ are each independently selected from hydrogen and    C₁₋₆alkyl, or    -   R⁹ and R¹⁰ taken together with the nitrogen atom to which they        are bound, form a 5- or 6-membered heterocyclic ring optionally        containing one additional heteroatom selected from oxygen,        sulfur and N—R¹⁵, wherein the ring may be substituted by up to        two C₁₋₆alkyl groups;-   R¹¹ is selected from hydrogen, C₁₋₆alkyl and    —(CH₂)_(q)—C₃₋₇cycloalkyl optionally substituted by one or more    C₁₋₆alkyl groups,-   R₁₂ is selected from hydrogen and C₁₋₆alkyl, or    -   R¹¹ and R¹² taken together with the nitrogen atom to which they        are bound, form a 5- or 6-membered heterocyclic ring optionally        containing one additional heteroatom selected from oxygen,        sulfur and NR¹⁵;-   R¹³ is selected from C₁₋₆alkyl, C₁₋₆alkoxy,    —(CH₂)_(q)—C₃₋₇cycloalkyl optionally substituted by one or more    C₁₋₆alkyl groups, —CONR⁹R¹⁰, —NHCOR¹⁰, halogen, —CN,    —(CH₂)_(s)NR¹¹R¹², trifluoromethyl, phenyl optionally substituted by    one or more R¹⁴ groups and heteroaryl optionally substituted by one    or more R¹⁴ groups;-   R¹⁴ is selected from C₁₋₆alkyl, C₁₋₆alkoxy, halogen, trifluoromethyl    and —NR¹¹R¹²;-   R¹⁵ is selected from hydrogen and methyl;-   X and Y are each independently selected from hydrogen, methyl and    halogen;-   Z is halogen;-   m is selected from 0, 1, 2, 3 and 4, wherein each carbon atom of the    resulting carbon chain may be optionally substituted with up to two    groups selected independently from C₁₋₆alkyl and halogen;-   n is selected from 0, 1 and 2;-   q is selected from 0, 1 and 2;-   r is selected from 0 and 1; and-   s is selected from 0, 1, 2 and 3.

In one embodiment, the p38 kinase inhibitor from Genus V is selectedfrom the following:

-   6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-cyclopropylmethyl-nicotinamide;-   6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(1-cyclopropylethyl)nicotinamide;-   6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)nicotinamide;-   6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2-methylpropyl)nicotinamide;    and-   6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(1-methylpropyl)nicotinamide.-   6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-cyclobutylmethyl-nicotinamide;-   6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-cyclobutyl-nicotinamide,-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2,4,5-trifluorobenzyl)nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2,5-difluorobenzyl)nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(3,4-difluorobenzyl)nicotinamide;-   N-(3-chlorobenzyl)-6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}nicotinamide;-   N-(4-chlorobenzyl)-6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}nicotinamide;-   N-(3-chloro-2-fluorobenzyl)-6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}nicotinamide;-   N-(2-chloro-3,6-difluorobenzyl)-6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2,3-difluoro-4-methylbenzyl)nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2,3,5-trifluorobenzyl)nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(3-fluoro-4-methylbenzyl)nicotinamide;-   N-(5-chloro-2-fluorobenzyl)-6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}nicotinamide;-   N-(2-chlorobenzyl)-6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(4-fluorobenzyl)nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2,3,4-trifluorobenzyl)nicotinamide;-   N-benzyl-6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[3-(trifluoromethyl)benzyl]nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(1,1-dimethylbutyl)nicotinamide;-   N-(4-chloro-2-fluorobenzyl)-6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[4-(trifluoromethyl)benzyl]nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(5-methyl-2-furyl)methyl]nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2,3-difluorobenzyl)nicotinamide;-   N-(3-chloro-4-fluorobenzyl)-6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(4-methylbenzyl)nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(3-methylthien-2-yl)methyl]nicotinamide;-   N-(3-chloro-2,6-difluorobenzyl)-6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(1-ethyl-1-methylpropyl)nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2-fluorobenzyl)nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(tert-pentyl)nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(3-methylbenzyl)nicotinamide;    and-   6-(5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl)-N-neopentylnicotinamide    (“Losmapimod”), Formula V′.

In one embodiment, the p38 kinase inhibitor is6-(5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl)-N-neopentylnicotinamide(“Losmapimod”), Formula V′.

Genus V Definitions

As used herein, the term “alkyl” refers to straight or branchedhydrocarbon chains containing the specified number of carbon atoms. Forexample, C1-6alkyl means a straight or branched alkyl containing atleast 1, and at most 6, carbon atoms. Examples of “alkyl” as used hereininclude, but are not limited to, methyl, ethyl, n-propyl, n-butyl,n-pentyl, isobutyl, isopropyl and t-butyl. A C1-4alkyl group ispreferred, for example methyl, ethyl, isopropyl or t-butyl. The saidalkyl groups may be optionally substituted with one or more fluorineatoms for example, trifluoromethyl.

As used herein, the term “alkenyl” refers to straight or branchedhydrocarbon chains containing the specified number of carbon atoms andcontaining at least one double bond. For example, C2-6alkenyl means astraight or branched alkenyl containing at least 2, and at most 6,carbon atoms and containing at least one double bond. Examples of“alkenyl” as used herein include, but are not limited to ethenyl,propenyl, 3-methylbut-2-enyl and 1,1-dimethylbut-2-enyl.

As used herein, the term “alkoxy” refers to a straight or branched chainalkoxy group, for example, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy,but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy, or hexyloxy.A C1-4alkoxy group is preferred, for example methoxy or ethoxy.

As used herein, the term “cycloalkyl” refers to a non-aromatichydrocarbon ring containing the specified number of carbon atoms whichmay optionally contain up to one double bond. For example,C3-7cycloalkyl means a non-aromatic ring containing at least three, andat most seven, ring carbon atoms. Examples of “cycloalkyl” as usedherein include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl. A C3-6cycloalkyl group ispreferred, for example, cyclopropyl, cyclopentyl or cyclohexyl. The saidcycloalkyl groups may be optionally substituted with one or moreC1-6alkyl groups, for example one or two methyl groups. In oneembodiment, the cycloalkyl groups may be optionally substituted by up tofour C1-6alkyl groups, for example one or two C1-6alkyl groups, inparticular one or two C1-4alkyl groups such as methyl or ethyl.

As used herein, the terms “heteroaryl ring” and “heteroaryl” refer to amonocyclic five- to seven-membered unsaturated hydrocarbon ringcontaining at least one heteroatom independently selected from oxygen,nitrogen and sulfur. Preferably, the heteroaryl ring has five or sixring atoms. Examples of heteroaryl rings include, but are not limitedto, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl,isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl andtriazinyl. The said ring may be optionally substituted by one or moresubstituents independently selected from C1-6alkyl and oxy.

As used herein, the terms “heterocyclic ring” or “heterocyclyl” refer toa monocyclic three- to seven-membered saturated hydrocarbon ringcontaining at least one heteroatom independently selected from oxygen,nitrogen and sulfur. Preferably, the heterocyclyl ring has five or sixring atoms. Examples of heterocyclyl groups include, but are not limitedto, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl,morpholino, tetrahydropyranyl, tetrahydrofuranyl, and thiomorpholino.The said ring may be optionally substituted by one or more substituentsindependently selected from C1-6alkyl and oxy.

As used herein, the terms “halogen” or “halo” refer to the elementsfluorine, chlorine, bromine and iodine. Preferred halogens are fluorine,chlorine and bromine. A particularly preferred halogen is fluorine orchlorine.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s)which occur and events that do not occur.

As used herein, the term “substituted” refers to substitution with thenamed substituent or substituents, multiple degrees of substitutionbeing allowed unless otherwise stated.

Genus VI Description

Compounds of Genus VI can be prepared according to the disclosure ofU.S. Pat. No. 7,582,652, which is herein incorporated herein byreference in its entirety.

Genus VI is characterized by compounds of Formula VI:

or stereoisomers thereof, isotopically-enriched compounds thereof,prodrugs thereof, solvates thereof, and pharmaceutically acceptablesalts thereof;wherein:

-   W is selected from:

-   X is N, or C—R¹;-   R is C₁-C₇ alkyl, C₃-C₇ cycloalkyl, (C₁-C₇ alkylene)-(C₃-C₇    cycloalkyl), —SO₂—(C₁-C₇ alkyl), or —SO₂—NR⁵R⁶;-   R¹ is hydrogen, amino, methyl, or —N═CH(NMe)₂;-   R² is phenyl optionally substituted with one or two substituents    independently selected from halo;-   R³ is hydrogen, C₁-C₇ alkyl, C₃-C₇ cycloalkyl, or phenyl optionally    substituted with one or two substituents independently selected from    halo and trifluoromethyl;-   R⁴ is hydrogen or C₁-C₇ alkyl; and-   R⁵ and R⁶ are independently selected from the group consisting of    C₁-C₇ alkyl.

In one embodiment, the p38 kinase inhibitor from Genus VI is selectedfrom the following:

-   5-(2-tert-Butyl-5-phenyl-3H-imidazol-4-yl)-3-(2,2-dimethylpropyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-(2,6-Difluorophenyl)-5-phenyl-3H-imidazol-4-yl]-3-(2,2-dimethylpropyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-(2-tert-Butyl-5-phenyl-3H-imidazol-4-yl)-3-cyclopropylmethyl-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-(2-Cyclopropyl-5-phenyl-3H-imidazol-4-yl)-3-(2,2-dimethylpropyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   3-(2,2-Dimethylpropyl)-5-[5-(4-fluorophenyl)-2-(2-fluoro-6-trifluoromethylphenyl)-3H-imidazol-4-yl]-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   3-(2,2-Dimethylpropyl)-5-[2-(2-fluoro-6-trifluoromethylphenyl)-5-phenyl-3H-imidazol-4-yl]-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-Cyclopropyl-5-(4-fluorophenyl)-3H-imidazol-4-yl]-3-(2,2-dimethylpropyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-(2,6-Difluorophenyl)-5-(4-fluorophenyl)-3H-imidazol-4-yl]-3-(2,2-dimethylpropyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-tert-Butyl-5-(4-fluorophenyl)-3H-imidazol-4-yl]-3-(2,2-dimethylpropyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-tert-Butyl-5-(4-fluorophenyl)-3H-imidazol-4-yl]-3-cyclopropylmethyl-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-tert-Butyl-5-(2,4-difluorophenyl)-3H-imidazol-4-yl]-3-(2,2-dimethylpropyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   R-5-[2-tert-Butyl-5-(4-fluorophenyl)-3H-imidazol-4-yl]-3-(1,2,2-trimethylpropyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   R-5-[2-(2,6-Difluorophenyl)-5-(4-fluorophenyl)-3H-imidazol-4-yl]-3-(1,2,2-trimethylpropyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   R-5-[5-(4-Fluorophenyl)-2-(2-fluoro-6-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-3-(1,2,2-trimethylpropyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   3-Cyclopropylmethyl-5-[2-(2,6-dichlorophenyl)-5-(4-fluorophenyl)-3H-imidazol-4-yl]-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   3-Cyclopropylmethyl-5-[2-(2,6-difluorophenyl)-5-(4-fluorophenyl)-3H-imidazol-4-yl]-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-(2,6-Dichlorophenyl)-5-(4-fluorophenyl)-3H-imidazol-4-yl]-3-(2,2-dimethylpropyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-(2-Chloro-6-fluorophenyl)-5-phenyl-3H-imidazol-4-yl]-3-(2,2-dimethylpropyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   3-Cyclopropylmethyl-5-[2-(2,6-difluorophenyl)-5-phenyl-3H-imidazol-4-yl]-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   3-Cyclopropylmethyl-5-[2-(2,6-dichlorophenyl)-5-phenyl-3H-imidazol-4-yl]-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[5-(2,4-Difluorophenyl)-2-(2,6-difluorophenyl)-3H-imidazol-4-yl]-3-(2,2-dimethylpropyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[3-(4-Fluorophenyl)-1-methylpyrazol-4-yl]-3H-3-isobutyl-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[5-(4-Fluorophenyl)-1-methylpyrazol-4-yl]-3H-3-isobutyl-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[3-(4-Fluorophenyl)-1-morpholinoethylpyrazol-4-yl]-3H-3-isobutyl-imidazo[4,5-b]pyridin-2-ylamine-methanesulfonate;-   5-[3-(4-Fluorophenyl)-pyrazol-4-yl]-3H-3-isobutyl-imidazo[4,5-b]pyridin-2-ylamine    di-methanesulfonate;-   3H-3-isobutyl-5-(3-phenyl-1-isopropylpyrazol-4-yl)-imidazo[4,5-b]pyridin-2-ylamine    di-methanesulfonate;-   3H-3-isobutyl-5-(3-phenyl-1-methylpyrazol-4-yl)-imidazo[4,5-b]pyridin-2-ylamine    di-methanesulfonate;-   3H-3-isobutyl-5-(3-phenyl-pyrazol-4-yl)-imidazo[4,5-b]pyridin-2-ylamine    di-methanesulfonate-   5-[3-(2,4-Difluorophenyl)pyrazol-4-yl]-3H-3-isobutyl-imidazo[4,5-b]pyridin-2-ylamine    di-methanesulfonate;-   5-[2-(2,6-Difluorophenyl)-5-phenyl-3H-imidazol-4-yl]-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-(2,6-Dichlorophenyl)-5-phenyl-3H-imidazol-4-yl]-3-(2,2-dimethylpropyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-(2,6-Dichlorophenyl)-5-phenyl-1H-imidazol-4-yl]-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-(2,6-Dichlorophenyl)-5-(4-fluorophenyl)-1H-imidazol-4-yl]-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-(2,6-Dichlorophenyl)-5-(2,4-difluorophenyl)-1H-imidazol-4-yl]-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   R-5-[2-(2-Chloro-6-fluorophenyl)-5-(4-fluorophenyl)-3H-imidazol-4-yl]-3-(1,2,2-trimethylpropyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-tert-Butyl-5-(4-fluorophenyl)-3H-imidazol-4-yl]-3-(2,2-dimethylpropyl)-2-methyl-3H-imidazo[4,5-b]pyridine    methanesulfonate;-   5-(2-tert-Butyl-5-phenyl-3H-imidazol-4-yl)-3-(2,2-dimethyl-propyl)-2-methyl-3H-imidazo[4,5-b]pyridine    methanesulfonate;-   5-[2-(2-Chloro-6-fluorophenyl)-5-phenyl-3H-imidazol-4-yl]-3-(2,2-dimethyl-propyl)-2-methyl-3H-imidazo[4,5-b]pyridine    methanesulfonate;-   5-[2-(2,6-Difluorophenyl)-5-phenyl-3H-imidazol-4-yl]-3-(2,2-dimethylpropyl)-2-methyl-3H-imidazo[4,5-b]pyridine    methanesulfonate;-   5-[2-(2,6-Difluorophenyl)-5-(4-fluorophenyl)-3H-imidazol-4-yl]-3-(2,2-dimethylpropyl)-2-methyl-3H-imidazo[4,5-b]pyridine    methanesulfonate;-   5-[2-(2,6-Dichlorophenyl)-5-(4-fluorophenyl)-3H-imidazol-4-yl]-3-(2,2-dimethylpropyl)-2-methyl-3H-imidazo[4,5-b]pyridine    methanesulfonate;-   3-Cyclopropylmethyl-5-[2-(2,6-difluorophenyl)-5-phenyl-3H-imidazol-4-yl]-2-methyl-3H-imidazo[4,5-b]pyridine    methanesulfonate;-   3-Cyclopropylmethyl-5-[2-(2,6-dichlorophenyl)-5-phenyl-3H-imidazol-4-yl]-2-methyl-3H-imidazo[4,5-b]pyridine    methanesulfonate;-   5-(2-Cyclopropyl-5-phenyl-3H-imidazol-4-yl)-3-(2,2-dimethylpropyl)-2-methyl-3H-imidazo[4,5-b]pyridine    methanesulfonate;-   5-[2-(2,6-Dichlorophenyl)-5-phenyl-3H-imidazol-4-yl]-3-(2,2-dimethylpropyl)-2-methyl-3H-imidazo[4,5-b]pyridine    methanesulfonate;-   5-[2-(2-Chloro-6-fluorophenyl)-5-phenyl-3H-imidazol-4-yl]-3-(2,2-dimethylpropyl)-3H-imidazo[4,5-b]pyridine    methanesulfonate;-   5-(2-Cyclopropyl-5-phenyl-3H-imidazol-4-yl)-3-(2,2-dimethylpropyl)-3H-imidazo    [4,5-b]pyridine methanesulfonate;-   5-[2-(2,6-Difluorophenyl)-5-phenyl-3H-imidazol-4-yl]-3-isobutyl-3H-imidazo[4,5-b]pyridine    methanesulfonate;-   5-[3-(4-Fluorophenyl)-1-isopropylpyrazol-4-yl]-3H-3-isobutylimidazo[4,5-b]pyridin-2-ylamine    di-methanesulfonate;-   5-[2-tert-Butyl-5-phenyl-1H-imidazol-4-yl]-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-ylamine    di-methanesulfonate;-   5-[2-(2-Fluoro-6-chlorophenyl)-5-phenyl-1H-imidazol-4-yl]-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-Cyclopropyl-5-phenyl-1H-imidazol-4-yl]-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-(2-Fluoro-6-trifluoromethylphenyl)-5-phenyl-1H-imidazol-4-yl]-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-(2-Fluoro-6-chlorophenyl)-5-(4-fluorophenyl-1H-imidazol-4-yl]-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-isopropyl-5-phenyl-1H-imidazol-4-yl]-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-ylamine    di-methanesulfonate;-   5-[2-(2-Fluoro-6-trifluoromethylphenyl)-5-(2,4-difluorophenyl-1H-imidazol-4-yl]-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-tert-Butyl)-5-(2,4-difluorophenyl-1H-imidazol-4-yl]-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-Isopropyl)-5-(2,4-difluorophenyl-1H-imidazol-4-yl]-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-(2-Fluoro-6-chlorophenyl)-5-(2,4-difluorophenyl-1H-imidazol-4-yl]-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-Cyclopropyl-5-(2,4-difluorophenyl)-1H-imidazol-4-yl]-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-Cyclopropyl-5-(4-fluorophenyl)-1H-imidazol-4-yl]-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-ylamine    di-methanesulfonate;-   5-[2-tert-Butyl-5-(4-fluorophenyl)-1H-imidazol-4-yl]-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-ylamine    di-methanesulfonate;-   N′-{5-[2-(2,6-Difluorophenyl)-5-phenyl-3H-imidazol-4-yl]-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-yl}-N,N-dimethylformamidine;-   5-[2-(2,6-Difluorophenyl)-3-methyl-5-phenyl-3H-imidazol-4-yl]-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-ylamine;-   5-[2-(2,6-Dichlorophenyl)-3-methyl-5-phenyl-3H-imidazol-4-yl]-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-ylamine;-   3-(2,2-Dimethylpropyl)-5-(5-phenyl-3H-[1,2,3]triazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   3-(2,2-Dimethylpropyl)-5-[5-(4-fluoro-phenyl)-3H-[1,2,3]triazol-4-yl]-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   3-Cyclopropylmethyl-5-[5-(4-fluoro-phenyl)-3H-[1,2,3]triazol-4-yl]-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   3-Cyclopropylmethyl-5-(5-phenyl-3H-[1,2,3]triazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-(2-Chloro-6-fluorophenyl)-5-phenyl-1H-imidazol-4-yl]-3-isobutyl-3H-[1,2,3]triazolo[4,5-b]pyridine    methanesulfonate;-   5-[2-(2,6-Dichlorophenyl)-5-phenyl-1H-imidazol-4-yl]-3-isobutyl-3H-[1,2,3]triazolo[4,5-b]pyridine    methanesulfonate;-   5-[2-(2,6-Dichlorophenyl)-5-(2,4-difluoro-phenyl)-1H-imidazol-4-yl]-3-isobutyl-3H-[1,2,3]triazolo[4,5-b]pyridine    methanesulfonate-   5-[2-tert-Butyl-5-(4-fluorophenyl)-1H-imidazol-4-yl]-3-isobutyl-3H-[1,2,3]triazolo[4,5-b]pyridine    methanesulfonate;-   2-Amino-5-(2-tert-butyl-5-phenyl-3H-imidazol-4-yl)imidazo[4,5-b]pyridine-3-sulfonic    acid dimethylamide methanesulfonate;-   2-Amino-5-[(2-fluoro-6-chlorophenyl)-5-phenyl-3H-imidazol-4-yl)]imidazo[4,5-b]pyridine-3-sulfonic    acid dimethyl-amide methanesulfonate;-   2-Amino-5-[(2,6-dichlorophenyl)-5-phenyl-3H-imidazol-4-yl)]imidazo[4,5-b]pyridine-3-sulfonic    acid dimethyl-amide methanesulfonate;-   2-Amino-5-(2-tert-butyl-5-(2,4-difluoro-phenyl)-3H-imidazol-4-yl)imidazo[4,5-b]pyridine-3-sulfonic    acid dimethyl-amide methanesulfonate;-   5-[2-(2,6-Difluorophenyl)-5-phenyl-3H-imidazol-4-yl]-3-(propane-2-sulfonyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   3-Butyl-5-[2-(2,6-difluorophenyl)-5-phenyl-3H-imidazol-4-yl]-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   3-Butyl-5-[2-(2-fluorophenyl)-5-phenyl-3H-imidazol-4-yl]-3H-imidazo[4,5-b]pyridin-2-ylamine,    di-methanesulfonate;-   3-Butyl-5-[2-(2-chloro-6-fluorophenyl)-5-phenyl-3H-imidazol-4-yl]-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   3-Butyl-5-(2-tert-butyl-5-phenyl-3H-imidazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   3-Butyl-5-[2-(2-fluoro-6-trifluoromethylphenyl)-5-phenyl-3H-imidazol-4-yl]-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   2-Amino-5-(5-(phenyl-2H-[1,2,3]triazol-4-yl)imidazo[4,5-b]pyridine-3-sulfonic    acid dimethylamide;-   5-[2-(2-Fluoro-6-trifluoromethylphenyl)-5-phenyl-3H-imidazol-4-yl]-3-(propane-2-sulfonyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-(2-tert-Butyl-5-phenyl-3H-imidazol-4-yl)-3-(propane-2-sulfonyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-(2,6-Dichlorophenyl)-5-phenyl-3H-imidazol-4-yl]-3-(propane-2-sulfonyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-(2-Chloro-6-fluorophenyl)-5-phenyl-3H-imidazol-4-yl]-3-(propane-2-sulfonyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   3-Butyl-5-[2-tert-butyl-5-(2,4-difluorophenyl)-3H-imidazol-4-yl]-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-tert-Butyl-4-(4-fluorophenyl)oxazol-5-yl]-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-ylamine;-   5-[2-tert-Butyl-4-(2,4-difluorophenyl)oxazol-5-yl]-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[4-(4-Fluorophenyl)-2-isopropyloxazol-5-yl]-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   3-Isobutyl-5-(2-methyl-4-phenylthiazol-5-yl)-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[4-(4-Fluorophenyl)-2-methylthiazol-5-yl]-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   2-Amino-5-(2-tert-butyl-5-(4-fluorophenyl)oxazol-5-yl)imidazo[4,5-b]pyridine-3-sulfonic    acid dimethylamide;-   2-Amino-5-(2-isopropyl-5-(4-fluorophenyl)    oxazol-5-yl)imidazo[4,5-b]pyridine-3-sulfonic acid dimethylamide    methane-sulfonate;-   5-[2-(2,6-Dichloro-phenyl)-5-(4-fluoro-phenyl)-1H-imidazol-4-yl]-3-(2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   3-(2,2-Dimethyl-propyl)-5-[5-(4-fluoro-phenyl)-2-(2-fluoro-6-trifluoromethyl-phenyl)-1H-imidazol-4-yl]-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-tert-Butyl-5-(2,4-difluoro-phenyl)-1H-imidazol-4-yl]-3-(2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-tert-Butyl-5-(4-fluoro-phenyl)-1H-imidazol-4-yl]-3-(2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-tert-Butyl-5-(4-fluoro-phenyl)-1H-imidazol-4-yl]-3-(2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    fumarate;-   5-[2-tert-Butyl-5-(4-fluoro-phenyl)-1H-imidazol-4-yl]-3-(2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    dimethanesulfonate;-   5-[2-tert-Butyl-5-(4-fluoro-phenyl)-1H-imidazol-4-yl]-3-(2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    succinate;-   5-[2-tert-Butyl-5-(4-fluoro-phenyl)-1H-imidazol-4-yl]-3-(2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    dimaleate;-   5-[2-tert-Butyl-5-(4-fluoro-phenyl)-1H-imidazol-4-yl]-3-(2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    dihydrochloride;-   5-[2-(2-Chloro-6-fluoro-phenyl)-5-phenyl-3H-imidazol-4-yl]-3-(2,2-dimethylpropyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-tert-Butyl-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-3-(1(R),2,2-trimethyl-propyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-(2,6-Difluoro-phenyl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-3-(1(R),    2,2-trimethyl-propyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    methanesulfonate;-   5-[2-tert-butyl-5-(4-fluoro-phenyl)-1H-imidazol-4-yl]-3-(2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    dimethanesulfonate    5-Bromo-3-(2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridin-2-yl-ammonium    bromide;-   5-[2-tert-butyl-5-(4-fluoro-phenyl)-1H-imidazol-4-yl]-3-(2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridin-2-ylamine    dimethanesulfonate    2-Amino-3-(2,2-dimethyl-propyl)-5-[2-(4-fluorophenyl)-2-oxo-acetyl]-3H-imidazo[4,5-b]pyridin-1-ium    methanesulfonate;-   5-(2-(tert-butyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-3-neopentyl-3H-imidazo[4,5-b]pyridin-2-amine    methanesulfonate (“LY2228820 salt”); and-   5-(2-(tert-butyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-3-neopentyl-3H-imidazo[4,5-b]pyridin-2-amine    (“LY2228820”), Formula VI′.

In one embodiment, the p38 kinase inhibitor is5-(2-(tert-butyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-3-neopentyl-3H-imidazo[4,5-b]pyridin-2-amine(“LY2228820”), Formula VI′.

In one embodiment, the p38 kinase inhibitor is5-(2-(tert-butyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-3-neopentyl-3H-imidazo[4,5-b]pyridin-2-aminemethanesulfonate (“LY2228820 salt”).

In one embodiment, the p38 kinase inhibitor is a dimesylate salt(“[CH₃S(O)₂OH]₂”) of LY2228820.

Genus VI Definitions

The general chemical terms used in the Formulae above have their usualmeanings. For example, the term “C1-C7 alkyl” includes methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyland heptyl moieties. The term “C1-C7 alkylene” includes methylene,ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene,tert-butylene, pentylene, hexylene and heptylene moieties. The term“C3-C7 cycloalkyl” includes cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl moieties. The term “(C1-C7 alkylene)-(C3-C7cycloalkyl)” is taken to mean a C3-C7 cycloalkyl attached through aC1-C7alkylene linker. The term “halo” includes fluoro, chloro, bromo,and iodo.

The skilled artisan will also appreciate that when variable “W” isimidazole (i), and R4 is hydrogen, the imidazole ring exists in thefollowing two tautomeric forms:

Although Tautomers I and II are structurally distinct, the skilledartisan will appreciate that they exist in equilibrium and are easilyand rapidly interconvertible under ordinary conditions. (See: March,Advanced Organic Chemistry, Third Edition, Wiley Interscience, New York,N.Y. (1985), pages 66-70; and Allinger, Organic Chemistry, SecondEdition, Worth Publishers, New York, N.Y., (1976), page 173) As such,the representation of a compound of Formula I, where variable “W” isimidazole (i) and R4 is hydrogen, in one tautomeric form contemplatesboth tautomeric forms of the imidazole ring. Likewise, the naming of acompound of Formula I where “W” is imidazole (i) and R4 is hydrogen aseither a 1H-imidazole or a 3H-imidazole contemplates both tautomericforms of the imidazole ring. Specifically, the name5-[2-tert-butyl-5-(4-fluoro-phenyl)-1H-imidazol-4-yl]-3-(2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridin-2-ylaminecontemplates the molecule in either the 1H-imidazol-4-yl or3H-imidazol-4-yl form. Similarly, when variable “W” is triazole (iv),the triazole moiety exists in three tautomeric forms, and therepresentation or naming of one tautomeric form contemplates all threetautomeric forms of the triazole ring.

Especially preferred are di-methanesulfonic acid salts of the compoundsof Formula VI.

Genus VII Description

Compounds of Genus VII can be prepared according to the disclosure ofU.S. Pat. No. 6,867,209, which is herein incorporated herein byreference in its entirety.

Genus VII is characterized by compounds of Formula VII:

or stereoisomers thereof, isotopically-enriched compounds thereof,prodrugs thereof, solvates thereof, and pharmaceutically acceptablesalts thereof;wherein:

represents a single or double bond;one of Y and Z is CA or CR⁸A and the other is CR¹, CR¹ ₂, NR⁶ or N;wherein:

-   -   each R¹ is independently hydrogen or is alkyl, alkenyl, alkynyl,        aryl, arylalkyl, acyl, aroyl, heteroaryl, —NH-aroyl, halo, —OR,        —NR₂, —SR, —S(O)R, —S(O)₂R, —OC(O)R, —NRC(O)R, —NRC(O)NR₂,        —NRC(O)OR, —OC(O)NR₂, —C(O)R, —C(O)OR, -alkyl-OC(O)R, —SO₃R,        —C(O)NR₂, —S(O)₂NR₂, —NRS(O)₂NR₂, —CN, —CF₃, —SiR₃, and —NO₂,    -   wherein:        -   each R is independently H, alkyl, alkenyl or aryl;

-   R⁶ is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, or    heteroaryl, or is —S(O)R, —S(O)₂R, —C(O)R, —C(O)OR, -alkyl-C(O)R,    —S(O)₂OR, —C(O)NR₂, —S(O)₂NR₂, —CN, —CF₃, or —SiR₃,    -   wherein:        -   each R is independently H, alkyl, alkenyl or aryl;

-   R⁸ is H, halo, alkyl or alkenyl;

-   A is —W_(i)—C(O)X_(j)Y,    -   wherein:        -   Y is C(O)R², and        -   wherein:            -   R² is hydrogen or is straight or branched chain alkyl,                alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, or                heteroarylalkyl, each optionally substituted with halo,                alkyl, —SR, —OR, —NR₂, —OC(O)R, —NRC(O)R, —NRC(O)NR₂,                —NRS(O)₂R, —NRS(O)₂NR₂, —OC(O)NR₂, —CN, —C(O)OR,                —C(O)NR₂, —C(O)R, or —SiR₃, wherein each R is                independently H, alkyl, alkenyl or aryl, or            -   R² is —OR, —NR₂, —NRCONR₂, —OC(O)NR₂, —NRS(O)₂NR₂,                heteroarylalkyl, —C(O)OR, —NRNR₂, heteroaryl,                heteroaryloxy, heteroaryl-NR, or NROR,            -   wherein:                -   each R is independently H, alkyl, alkenyl or aryl,                    or                -    two R attached to the same N atom may form a 3-8                    member ring selected from the group consisting of a                    piperazine ring, a morpholine ring, a thiazolidine                    ring, an oxazolidine ring, a pyrrolidine ring, a                    piperidine ring, an azacyclopropane ring, an                    azacyclobutane ring and an azacyclooctane ring; and                -    wherein said ring is optionally substituted with                    alkyl, alkenyl, alkynyl, aryl, arylalkyl,                    heteroaryl, heteroarylalkyl, each optionally                    substituted with halo, —SR, —OR, —NR₂, —OC(O)R,                    —NRC(O)R, —NRC(O)NR₂, —NRS(O)₂R, —NRS(O)₂NR₂,                    —OC(O)NR₂, or —SiR₃,                -    wherein:                -    each R is independently H, alkyl, alkenyl, or aryl,                    or                -    two R attached to the same N atom may form a 3-8                    member ring, optionally substituted as above                    defined, and

-   each of W and X is substituted or unsubstituted alkylene, alkenylene    or alkynylene, each of 2-6 Å or

-   Y is tetrazole; 1,2,3-triazole; 1,2,4-triazole; or imidazole, and

-   each of i and j is independently 0 or 1;

-   R⁷ is H or is alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl,    heteroaryl, —S(O)R, —S(O)₂R, —C(O)R, —C(O)OR, -alkyl-COR, —S(O)₂OR,    —C(O)NR₂, —S(O)₂NR₂, —CN, —CF₃, —NR₂, —OR, -alkyl-SR, -alkyl-S(O)R,    -alkyl-S(O)₂R, -alkyl-OC(O)R, -alkyl-C(O)OR, -alkyl-CN,    -alkyl-C(O)NR₂, or —SiR₃,    -   wherein each R is independently H, alkyl, alkenyl or aryl or R⁷        is methoxymethyl, methoxyethyl, ethoxymethyl, benzyloxymethyl,        or 2-methoxyethyloxy methyl;

-   each R³ is independently halo, alkyl, —OC(O)R, —OR, —NRC(O)R, —SR,    or —NR₂, wherein R is H, alkyl or aryl;

-   n is 0-3;

-   L¹ is —C(O)—, —S(O)₂—, or alkylene (1-4C);

-   L² is alkylene (1-4C) or alkenylene (2-4C) optionally substituted    with one or two moieties selected from the group consisting of    alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl,    —NH-aroyl, halo, —OR, —NR₂, —SR, —S(O)R, —S(O)₂R, —OC(O)R, —NRC(O)R,    —NRC(O)NR₂, —NRC(O)OR, —OC(O)NR₂, —C(O)R, —C(O)OR, -alkyl-OC(O)R,    —S(O)₂OR, —C(O)NR₂, —S(O)₂NR₂, —NRS(O)₂NR₂CN, —CF₃, and —SiR₃,    -   wherein each R is independently H, alkyl, alkenyl or aryl, and        wherein two substituents on L² can be joined to form a        non-aromatic saturated or unsaturated ring that includes 0-3        heteroatoms which are 0, S and/or N and which contains 3 to 8        members or said two substituents can be joined to form a        carbonyl moiety or an oxime, oximeether, oximeester or ketal of        said carbonyl moiety;

-   each R⁴ is independently selected from the group consisting of    alkyl, alkenyl, alkynyl, aryl arylalkyl, acyl, aroyl, heteroaryl,    —NH-aroyl, halo, —OR, —NR₂, —SR, —SOR, —SO₂R, —OCOR, —NRCOR,    —NRCONR₂, —NRCOOR, —OCONR₂, —RCO, —COOR, -alkyl-OOCR, —SO₃R, —CONR₂,    —SO₂NR₂, —NRSO₂NR₂, —CN, —CF₃, —SiR₃, and —NO₂, or    -   two R⁴ on adjacent positions can be joined to form a fused,        optionally substituted aromatic or nonaromatic, saturated or        unsaturated ring which contains 3-8 members, or R⁴ is ═O or an        oxime, oximeether, oximeester or ketal thereof    -   wherein each R is independently H, alkyl, alkenyl or aryl;

-   m is 0-4;

-   Ar is an aryl group substituted with 0-5 substituents selected from    the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl,    acyl, aroyl, heteroaryl, —NH-aroyl, halo, —OR, —NR₂, —SR, —S(O)R,    —S(O)₂R, —OC(O)R, —NRC(O)R, —NRC(O)NR₂, —NRC(O)OR, —OC(O)NR₂,    —C(O)R, —C(O)OR, -alkyl-OC(O)R, —S(O)₂OR, —C(O)NR₂, —S(O)₂NR₂,    —NRS(O)₂NR₂, —CN, —CF₃, —SiR₃, and —NO₂, wherein each R is    independently H, alkyl, alkenyl or aryl, and wherein two of said    optional substituents on adjacent positions can be joined to form a    fused, optionally substituted aromatic or nonaromatic, saturated or    unsaturated ring which contains 3-8 members.

In one embodiment, the p38 kinase inhibitor from Genus VII is selectedfrom the following:

-   1-methyl-6-methoxy-[4′-fluoro-(4-benzyl-2,5-dimethyl    piperazinyl)]-indole-5-carboxamide-3-N,N-dimethyl glyoxalicamide;-   1-methyl-6-chloro-[4′-fluoro-(4-benzyl-2,5-dimethyl    piperazinyl)]-indole-5-carboxamide-3-N,N-dimethyl glyoxalicamide;-   1-methyl-6-chloro-[4′-fluoro-(4-benzyl-2R,5S-dimethyl    piperazinyl)]-indole-5-carboxamide-3-N,N-dimethyl glyoxalicamide;-   1-methyl-6-chloro-[4′-fluoro-(4-benzyl-2R,5S-dimethyl    piperazinyl)]-indole-5-carboxamide-3-glyoxalicamide;-   1-methyl-6-chloro-[4′-fluoro-(4-benzyl-2R,5S-dimethyl    piperazinyl)]-indole-5-carboxamide-3-N-methyl-glyoxalicamide;-   1-methyl-6-methoxy-[4′-fluoro-(4-benzyl-2R,5 S-dimethyl    piperazinyl)]-indole-5-carboxamide-3-N,N-dimethyl glyoxalicamide;-   1-methyl-6-chloro-[4′-fluoro-(4-benzyl-2R,5S-dimethyl    piperazinyl)]-indole-5-carb oxamide-3-gly oxalic    acid-morpholinamide; and-   1-methyl-6-methoxy-[4′-fluoro-(4-benzyl-2R,5 S-dimethyl    piperazinyl)]-indole-5-carboxamide-3-glyoxalic acid-morpholinamide.

In one embodiment, the p38 kinase inhibitor is selected from thefollowing Compounds 1-182:

In one embodiment, 2-(6-chloro-5-((2R,5S)-4-(4-fluorobenzyl)-2,5-dimethylpiperazine-1-carbonyl)-1-methyl-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide(“SCIO-469”), Formula VI′.

Genus VII Definitions

As used herein, the term “alkyl,” “alkenyl” and “alkynyl” includestraight- and branched-chain and cyclic monovalent substituents.Examples include methyl, ethyl, isobutyl, cyclohexyl, cyclopentylethyl,2-propenyl, 3-butynyl, and the like. Typically, the alkyl, alkenyl andalkynyl substituents contain 1-10C (alkyl) or 2-10C (alkenyl oralkynyl). Preferably they contain 1-6C (alkyl) or 2-6C (alkenyl oralkynyl). Heteroalkyl, heteroalkenyl and heteroalkynyl are similarlydefined but may contain 1-2 O, S or N heteroatoms or combinationsthereof within the backbone residue.

As used herein, “acyl” encompasses the definitions of alkyl, alkenyl,alkynyl and the related hetero-forms which are coupled to an additionalresidue through a carbonyl group.

“Aromatic” moiety refers to a monocyclic or fused bicyclic moiety suchas phenyl or naphthyl; “heteroaromatic” also refers to monocyclic orfused bicyclic ring systems containing one or more heteroatoms selectedfrom O, S and N. The inclusion of a heteroatom permits inclusion of5-membered rings as well as 6-membered rings. Thus, typical aromaticsystems include pyridyl, pyrimidyl, indolyl, benzimidazolyl,benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl,thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl and the like.Any monocyclic or fused ring bicyclic system which has thecharacteristics of aromaticity in terms of electron distributionthroughout the ring system is included in this definition. Typically,the ring systems contain 5-12 ring member atoms.

Similarly, “arylalkyl” and “heteroalkyl” refer to aromatic andheteroaromatic systems which are coupled to another residue through acarbon chain, including substituted or unsubstituted, saturated orunsaturated, carbon chains, typically of 1-6C. These carbon chains mayalso include a carbonyl group, thus making them able to providesubstituents as an acyl moiety.

Genus VIII Description

Compounds of Genus VIII can be prepared according to the disclosure ofU.S. Pat. No. 6,319,921, which is herein incorporated herein byreference in its entirety.

Genus VIII is characterized by compounds of Formula VIII:

or a stereoisomer thereof, an isotopically-enriched compound thereof, aprodrug thereof, a solvate thereof, or a pharmaceutically acceptablesalt thereof,wherein

-   Ar₁ is pyrazole optionally substituted by one or more R₁, R₂ or R₃;-   Ar₂ is phenyl, naphthyl quinoline, isoquinoline, tetahydronaphthyl,    tetahydroquinoline, tetrahydroisoquinoline, benzimidazole,    benzofuran, indanyl, indenyl or indole each being optionally    substituted with one to three R₂ groups;-   L is a C₁₋₁₀ saturated or unsaturated branched or unbranched carbon    chain;    -   wherein one or more methylene groups are optionally        independently replaced by O, N or S; and    -   wherein said linking group is optionally substituted with 0-2        oxo groups and one or more C₁₋₄ branched or unbranched alkyl        which may be substituted by one or more halogen atoms;-   Q is selected from the group consisting of:    -   a) pyridine, pyrimidine, pyridzine, imidazole, benzimidazole,        oxazo[4,5-b]pyridine and imidazo[4,5-b]pyridine, which are        optionally substituted with one to three groups selected from        the group consisting of halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy,        hydroxy, mono- or di-(C₁₋₃ alkyl)amino, C₁₋₆ alkyl-S(O)_(m) and        phenylamino wherein the phenyl ring is optionally substituted        with one to two groups selected from the group consisting of        halogen, C₁₋₆ alkyl and C₁₋₆ alkoxy;    -   b) morpholine, thiomophorline, thiomorpholine sulfoxide,        thiomorpholine sulfone, piperidine, piperidinone and        tetrahydropyrrimidone which are optionally substituted with one        to three groups selected from the group consisting of C₁₋₆alkyl,        C₁₋₆ alkoxy, hydroxy, mono- or di-(C₁₋₃ alkyl)amino-C₁₋₃ alkyl,        phenylamino-C₁₋₃ alkyl and C₁₋₃ alkoxy-C₁₋₃ alkyl;-   R₁ is selected from the group consisting of:    -   a) C₃₋₁₀ branched or unbranched alkyl, which may optionally be        partially or fully halogenated, and optionally substituted with        one to three phenyl, naphthyl or heterocyclic groups selected        from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl,        pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl,        isoxazolyl and isothiazolyl; each such phenyl, naphthyl or        heterocycle selected from the group hereinabove described, being        substituted with 0 to 5 groups selected from the group        consisting of halogen, C₁₋₆ branched or unbranched alkyl which        is optionally partially or fully halogenated, C₃₋₈ cycloalkyl,        C₅₋₈ cycloalkenyl, hydroxy, cyano, C₁₋₃ alkyloxy which is        optionally partially or fully halogenated, NH₂C(O) and        di(C₁₋₃)alkylaminocarbonyl;    -   b) C₃₋₇ cycloalkyl selected from the group consisting of        cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl,        cycloheptanyl, bicyclopentanyl, bicyclohexanyl and        bicycloheptanyl, which may optionally be partially or fully        halogenated and which may optionally be substituted with one to        three C₁₋₃ alkyl groups, or an analog of such cycloalkyl group        wherein one to the ring methylene groups are replaced by groups        independently selected from O, S, CHOH, >C═O, >C═S and NH;    -   c) C₃₋₁₀ branched alkenyl which may optionally be partially or        fully halogenated, and which is optionally substituted with one        to three C₁₋₅ branched or unbranched alkyl, phenyl, naphthyl or        heterocyclic groups, with each such heterocyclic group being        independently selected from the group consisting of pyridinyl,        pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl,        pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each        such phenyl naphthyl or heterocyclic group being substituted        with 0 to 5 groups selected from halogen, C₁₋₆ branched or        unbranched alkyl which is optionally partially or fully        halogenated, cyclopropyl, cyclobutyl, cyclopentanyl,        cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and        bicycloheptanyl, hydroxy, cyano, C₁₋₃alkyloxy which is        optionally partially or fully halogenated, NH₂C(O), mono- or        di(C₁₋₃)alkylaminocarbonyl;    -   d) C₅₋₇ cycloalkenyl selected from the group consisting of        cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,        cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein        such cycloalkenyl group may optionally be substituted with one        to three C₁₋₃ alkyl groups;    -   e) cyano; and,    -   f) methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl;-   R₂ is selected from the group consisting of:    -   a) C₁₋₆ branched or unbrenched akyl which may optionally be        partially or fully halogenated, acetyl, aroyl, C₁₋₄ branched or        unbranched alkoxy, which may optionally be partially or fully        halogenated, halogen, methoxycarbonyl and phenylsulfonyl;-   R₃ is selected from the group consisting of:    -   a) a phenyl, naphthyl or heterocyclic group selected from the        group consisting of pyridinyl, pyrimidinyl, pyrazinyl,        pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl,        tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl,        isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,        benzoxazolyl, benzisoxazolyl, benzopyrazolyl, benzothiofuranyl,        cinnolinyl, pteridinyl, phthalazinyl, naphthpyridinyl,        quinoxalinyl, quinazolinyl, purinyl and indazolyl; wherein such        phenyl, naphthyl or heterocyclic group is optionally substituted        with one to five groups selected from the group consisting of a        C₁₋₆ branched or unbranched alkyl, phenyl naphthyl, heterocycle        selected from the group hereinabove described, C₁₋₆ branched or        unbranched alkyl which is optionally partially or fully        halogenated, cyclopropyl, cyclobutyl, cyclopentanyl,        cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl,        bicycloheptanyl, phenyl C₁₋₅alkyl, naphthyl C₁₋₅ alkyl, halo,        hydroxy, cyano, C₁₋₃ alkyloxy which may optionally be partially        or fully halogenated, phenyloxy, naphthyloxy, heteroaryl wherein        the heterocyclic moiety is selected from the group hereinabove        described, nitro, amino, mono- or di-(C₁₋₃)alkylamino,        phenylamino, naphthylamino, heterocyclylamino,    -   wherein the heterocyclyl moiety is selected from the group        hereinabove described, NH₂C(O), a mono- or di-(C₁₋₃)alkyl        aminocarbonyl, C₁₋₅ alkyl-C(O)—C₁₋₄ alkyl, amino-C₁₋₅ alkyl,        mono- or di-(C₁₋₃)alkylamino-C₁₋₅ alkyl, amino-S(O)₂,        di-(C₁₋₃)alkylamino-S(O)₂, R₄—C₁₋₅ alkyl, R₅—C₁₋₅ alkoxy,        R₆—C(O)—C₁₋₅ alkyl and R₇—C₁₋₅ alkyl(R₈)N;    -   b) a fused aryl selected from the group consisting of        benzocyclobutanyl, indanyl, indanyl, dihydronaphthyl,        tetahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or        a fused heterocyclyl selected from the group consisting of        cyclopentenopyridine, cyclohexanopyridine,        cyclopentanopyrimidine, cyclohexanopyrimidine,        cyclopentanopyrazine, cyclohexanopyrazine,        cyclopentanopyridazine, cyclohexanopyridazine,        cyclopentanoquinoline, cyclohexanoquinoline,        cyclopentanoisoquinoline, cyclohexanoisoquinoline,        cyclopentanoindole, cyclohexanoindole,        cyclopentanobenzimidazole, cyclohexanobenzimidazole,        cyclopentanobenzoxazole, cyclohexanobenzoxazole,        cyclopentanoimidazole, cyclohexanoimidazole,        cyclopentanothiophene and cyclohexanothiophene,    -   wherein the fused aryl or fused heterocyclyl ring is substituted        with 0 to 3 groups independently selected from phenyl naphthyl        and heterocyclyl selected from the group consisting of        pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,        imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, and        isothiazolyl, C₁₋₆ branched or unbranched alkyl which is        optionally partially or fully halogenated, halo, cyano, C₁₋₃        alkyloxy which is optionally partially or fully halogenated,        phenyloxy, naphthyloxy, heterocyclyloxy wherein the heterocyclyl        moiety is selected from the group hereinabove described, nitro,        amino, mono- or di-(C₁₋₃)alkylamino, phenylamino, naphthylamino,        heterocyclylamino,    -   wherein the heterocyclyl moiety is selected from the group        hereinabove described, NH₂C(O), a mono- or di-(C₁₋₃)alkyl        aminocarbonyl, C₁₋₄ alkyl-OC(O), C₁₋₅ alkyl-C(O)—C₁₋₄ branched        or unbranched alkyl, an amino-C₁₋₅ alkyl, mono- or or        di-(C₁₋₃)alkylamino-C₁₋₅ alkyl, R₉—C₁₋₅alkyl, R₁₀—C₁₋₅alkoxy,        R₁₁—C(O)—C₁₋₅ alkyl and R₁₂—C₁₋₅alkyl(R₁₃)N;    -   c) cycloalkyl selected from the group consisting of        cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,        bicyclohexanyl and bicycloheptanyl, wherein the cycloalkyl is        optionally partially or fully halogenated and which may        optionally be substituted with one to three C₁₋₃ alkyl groups;    -   d) C₅₋₇ cycloalkenyl, selected from the group consisting of        cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,        cycloheptadienyl, bicyclohexenyl and bicycloheptenyl,    -   wherein such cycloalkenyl group is optionally substituted with        1-3 C₁₋₃ alkyl groups; e) acetyl, aroyl, alkoxycarbonylalkyl or        phenylsulfonyl; and    -   f) C₁₋₆ branched or unbranched alkyl is optionally be partially        or fully halogenated; or R₁ and R₂ are taken together to form a        fused phenyl or pyridinyl ring;-   each of R₈ and R13 are independently selected from the group    consisting of hydrogen and C₁₋₄ branch or unbranched alkyl which may    optionally be partially or fully halogenated;-   each R₄, R₅, R₆, R₇, R₉, R₁₀, R₁₁ and R₁₂ is independently selected    from the group consisting of morpholine, piperidine, piperazine,    imidazole and tetrazole;-   m=0, 1 or 2; and-   X═O or S.

In one embodiment, the p38 kinase inhibitor from Genus VIII is selectedfrom the following:

-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(cis-2,6-dimethylmorpholin-4-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(trans-2,6-dimethylmorpholin-4-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(2-(methoxymethylemorpholin-4-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl)-2-oxoethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl)-2-methylethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl)-1-methylethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-thiomorpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(1-oxothiomorpholin-4-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)-3-methylnaphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-piperidin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(1-acetylpiperidin-4-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-thiazolidin-3-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl-carbonyloxo)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(tetrahydropyran-4-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(N-methyl-2-methoxyethylamino)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(1-oxo-tetrahydrothiophen-3-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-morpholin-4-yl-propyl)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(morpholin-4-yl-methyl)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-thiazolidin-3-yl-propyl)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(tetrahydropyran-2-yl-oxy)propyl)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl-ethyl)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl-ethenyl)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl)propyn-1-yl)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(tetrahydropyran-2-yl-oxy)propyn-1-yl)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(methoxymethyloxy)propyn-1-yl)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl)-3-methylpropyn-1-yl)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl)-3,3-dimethylpropyn-1-yl)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(tetrahydropyran-2-yl-oxy)butyn-1-yl)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(furan-2-ylcarbonyloxy)propyn-1-yl)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(piperdin-1-yl)propyn-1-yl)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(2-methoxymethylmorpholin-4-yl)propyn-1-yl)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yl-methoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-pyridin-4-yl-propoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-imidazol-1-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-benzimidazol-1-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(3,4-dimethoxyphenyl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yl-methylamino)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yl-carbonylamino)napthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(morpholin-4-yl-acetamido)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(pyridin-3-yl-methylamino)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(pyridin-3-yl-carbonylamino)naphthalen-1-yl]-urea;-   1-[5-iso-Propyl-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-(Tetrahydropyran-3-yl)-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-cyclohexyl-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-(2,2,2-trifluoroethyl)-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-(1-methylcycloprop-1-yl)-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-ethoxy)naphthalen-1-yl]-urea;-   1-[5-ethoxycarbonyl-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-(1-methylcyclohex-1-yl)-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-benzyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(4-chlorophenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl)-urea;-   1-[5-tert-butyl-2-butyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(ethoxycarbonylmethyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(4-methyl-3-carbamylphenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(4-methyl-3-(2-ethoxycarbonylvinyl)phenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(4-methyl-3-(morpholin-4-yl)methylphenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(4-methyl-3-dimethylaminomethylphenyl)-2H-pyrazol-3-yl]-3-4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(3-(2-morpholin-4-yl-ethyl)phenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(3-(tetrahydropyran-4-ylamino)phenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(3-dimethylaminomethylphenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(4-(tetrahydropyran-4-ylamino)phenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(4-(3-benzylureido)phenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(2-chloropyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphtlalen-1-yl]-urea;-   1-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(trans-2,6-dimethylmorpholin-4-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(3-morpholin-4-yl-propyn-1-yl)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(2-dimethylaminomethylmorpholin-4-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-iso-propyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-cyclopropyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(thiophen-3-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-cyclopentyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-iso-propyl-2H-pyrazol-3-yl]-3-[4-(tetrahydropyran-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-cyclopropyl-2H-pyrazol-3-yl]-3-[4-(1-oxo-tetrahydrothiophen-3-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(thiophen-3-yl)-2H-pyrazol-3-yl]-3-[4-(2-pyridinyl-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-cyclopentyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yl-methoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(pyridin-4-yl)propyn-1-yl)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(2-methylaminopyridin-4-yl)propyn-1-yl)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(1-oxo-tetrahydrothiophen-3-yl)propyn-1-yl)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(thiazolidin-3-yl)propyn-1-yl)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(tetrahydropyran-4-yl)propyn-1-yl)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-methylaminopyrimidin-4-yl-methoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(2-methylaminopyrimidin-4-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(4-methoxybenzimidazol-1-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(4-methylaminobenzimidazol-1-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(2-imidazo[4,5-b]pyridin-1-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-[1,8]naphthyridin-4-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(3,4-dihydro-2H-pyrano[2,3-b]pyridin-5-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-pyridin-3-yl-2H-pyrazol-3-yl]-3-[4-(2-methylaminopyrimidin-4-methoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(2-methylaminopyrimidin-4-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(4-methoxybenzimidazol-1-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(4-methylaminobenzimidazol-1-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(2-imidazo[4,5b]pyridin-1-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-[1,8]naphthyridin-4-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(3,4-dihydro-2H-pyrano[2,3-b]pyridin-5-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-cyclopropyl-2H-pyrazol-3-yl]-3-[4-(2-methylaminopyrimidin-4-yl-methoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-cyclopropyl-2H-pyrazol-3-yl]-3-[4-(2-(2-methylaminopyrimidin-4-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-cyclopropyl-2H-pyrazol-3-yl]-3-[4-(2-(4-methoxybenzimidazol-1-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-cyclopropyl-2H-pyrazol-3-yl]-3-[4-(2-(4-methylaminobenzimidazol-1-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(2-(2-imidazo[4,5-b]pyridin-1-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(2-[1,8]naphthyridin-4-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(2-(3,4-dihydro-2H-pyrano[2,3-b]pyridin-5-yl)ethoxy)naphthalen-1-yl]-urea-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(cis-2,6-dimethylmorpholin-4-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(trans-2,6-dimethylmorpholin-4-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(2-(methoxymethyl)morpholin-4-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl)-2-oxoethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl)-2-methylethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl)-1-methylethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-thiomorpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(1-oxothiomorpholin-4-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)-3-methylnaphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl-carbonyloxo)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(tetrahydropyran-4-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(1-oxo-tetrahydrothiophen-3-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-morpholin-4-yl-propyl)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(morpholin-4-yl-methyl)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl-ethyl)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl)propyn-1-yl)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(tetrahydropyran-2-yl-oxy)propyn-1-yl)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(tetrahydropyran-2-yl-oxy)butyn-1-yl)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(piperdin-1-yl)propyn-1-yl)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(2-methoxymethylmorpholin-4-yl)propyn-1-yl)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yl-methoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-pyridin-4-yl-propoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-imidazol-1-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(3,4-dimethoxyphenyl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yl-methylamino)naphthalen-1-yl]-urea;-   1-[5-iso-Propyl-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-cyclohexyl-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-(2,2,2-trifluoroethyl)-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-(1-methylcycloprop-1-yl)-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-(1-methylcyclohex-1-yl)-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(4-chlorophenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-butyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(4-methyl-3-carbamylphenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(4-methyl-3-(morpholin-4-yl)methylphenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(4-methyl-3-dimethylaminomethylphenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(3-dimethylaminomethylphenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(2-chloropyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(trans-2,6-dimethylmorpholin-4-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(3-morpholin-4-yl-propyn-1-yl)naphthalen-1-yl]-urea.-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(1-oxothiomorpholin-4-yl)ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;-   1-[5-tert-butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;    and-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-(2-morpholinoethoxy)naphthalen-1-yl)urea    (“Doramapimod”), Formula VIII′.

In one embodiment, the p38 kinase inhibitor is1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-(2-morpholinoethoxy)naphthalen-1-yl)urea(“Doramapimod”), Formula VIII′.

Genus VIII Definitions

The term “aroyl” as used in the present specification shall beunderstood to mean “benzoyl” or “naphthoyl”.

Genus IX Description

Compounds of Genus IX can be prepared according to the disclosures ofU.S. Pat. Nos. 7,160,883, 7,462,616, and 7,759,343 which are hereinincorporated herein by reference in their entireties.

Genus IX is characterized by compounds of Formula IX:

or stereoisomers thereof, isotopically-enriched compounds thereof,prodrugs thereof, solvates thereof, and pharmaceutically acceptablesalts thereof;wherein:

-   X is selected from —O—; —OC(═O)—, —S—, —S(═O)—, —SO₂—, —C(═O)—,    —CO₂—, —NR₈—, —NR₈C(═O)—, —NR₈C(═O)NR₉—, —NR₈CO₂—, —NR₈SO₂—,    —NR₈SO₂NR₉—, —SO₂NR—, —C(═O)NR₈—, halogen, nitro, and cyano, or X is    absent;-   Y is —C(═O)NH—, —NR_(10a)CO—B^(a), —NR₁₀CO₂—B^(aa), —NR₁₀SO₂ or    —SO₂NR₁₀;    -   B^(a) and B^(aa) are each independently selected from the group        consisting of a C₃₋₇ cycloalkyl, a 5-membered heteroaryl, and a        5-6 membered heterocyclo, wherein the C₃₋₇ cycloalkyl,        5-membered heteroaryl, or 5-6 membered heteroaryl, or 5-6        membered heterocyclo is optionally substituted with 1-2 R₇;        -   wherein:            -   (a) R is attached to any available carbon or nitrogen                atom of B^(a) or B^(aa) when B^(a) or B^(aa) is a                substituted cycloalkyl, a substituted heterocyclo or a                substituted heteroaryl, and            -   (b) at each occurrence R⁷ is independently selected from                the group consisting of keto (═O), alkyl, substituted                alkyl, halogen, haloalkoxy, ureido, cyano, —SR₂₀, —OR₂₀,                —NR₂₀R₂₁, —NR₂₀SO₂R₂₁, —SO₂R₁₉, —SO₂NR₂₀R₂₁, —CO₂R₂₀,                —C(═O)R₂₀, —C(═O)NR₂₀R₂₁, —OC(═O)R₂₀, —OC(═O)NR₂₀R₂₁,                —NR₂₀C(═O)R₂₁, —NR₂₀CO₂R₂₁, aryl, cycloalkyl,                heterocycle, and heteroaryl; and/or            -   (c) when B^(a) or B^(aa) is cycloalkyl, two R₇ groups                may join to form an optionally-substituted carbon-carbon                bridge of three to four carbon atoms, or two R₇ groups                may join to form a fused carbocyclic, heterocyclic or                heteroaryl ring, said fused ring being in turn                optionally substituted with one to three of R₂₂;-   B is optionally-substituted cycloalkyl, optionally-substituted    heterocyclo, or optionally-substituted heteroaryl; or aryl    substituted with one R₁₁ and 0-2 R₁₂, or    -   B is selected from —C(═O)R₁₃, —CO₂R₁₃, and —C(═O)NR₁₃R_(13a);-   R₁ and R₅ are independently selected from hydrogen, alkyl,    substituted alkyl, —OR₁₄, —SR₁₄, —OC(═O)R₁₄, —CO₂R₁₄,    —C(═O)NR₁₄R_(14a), —NR₁₄R_(14a), —S(═O)R₁₄, —SO₂R₁₄,    —SO₂NR₁₄R_(14a), —NR₁₄SO₂NR_(14a)R_(14b), —NR_(14a)SO₂R₁₄,    —NR₁₄C(═O)R_(14a), —NR₁₄CO₂R_(14a), —NR₁₄C(═O)NR_(14a)R_(14b),    halogen, nitro, and cyano;-   R₂ is hydrogen or C₁₋₄alkyl;-   R3 is hydrogen, methyl, perfluoromethyl, methoxy, halogen, cyano,    —NH₂, or —NH(CH₃);-   R₄ is selected from:    -   a) hydrogen, provided that R₄ is not hydrogen if X is —S(═O)—,        —SO₂—, —NR₈CO₂—, or —NR₈SO₂—;    -   b) alkyl, alkenyl, and alkynyl, any of which may be optionally        substituted with keto and/or one to four R₁₇;    -   c) aryl and heteroaryl, either of which may be optionally        substituted with one to three R₁₆; and    -   d) heterocyclo and cycloalkyl, either of which may be optionally        substituted with keto and/or one to three R₁₆; or    -   R₄ is absent if X is halogen, nitro, or cyano;-   R₆ is attached to any available carbon atom of phenyl ring and at    each occurrence is independently selected from alkyl, halogen,    —OCF₃, —CF₃, —OH, —C(═O)R^(e), —OC(═O)R^(e), —SH, —NHC(═O)NH₂, —NO₂,    —CN, —CO₂H, —R^(f)CO₂H, —C(═O)NH₂, —C(═O)OR^(e), —S(═O)R^(e),    —S(═O)(aryl), —NHSO₂(aryl), —NHSO₃(aryl), —NHSO₂R^(e), —SO₃H,    —SO₂(R^(e)), —SO₃(R^(e)), —SO₂NH₂, phenyl, benzyl, —O(aryl), and    —O(benzyl),    -   wherein:        -   R^(e) is alkyl, and        -   R^(f) is alkylene, and each alkyl, alkylene, aryl or benzyl            group of R₆ in turn may be further substituted by one to two            R₁₈;-   R₈ and R₉ are independently selected from hydrogen, alkyl,    substituted alkyl, aryl, cycloalkyl, heterocyclo, and heteroaryl;-   R₁₀ and R_(10a) are each independently selected from the group    consisting of hydrogen, alkyl, substituted alkyl, alkoxy, and aryl;-   R₁₁ is selected from optionally-substituted cycloalkyl,    optionally-substituted heterocyclo, and optionally-substituted    heteroaryl;-   R₁₂ is selected from alkyl, R₁₇, and C₁₋₄alkyl substituted with keto    (═O) and/or one to three R₁₇;-   R₁₃ and R_(13a) are independently selected from hydrogen, alkyl, and    substituted alkyl;-   R₁₄, R_(14a) and R_(14b) are independently selected from hydrogen,    alkyl, substituted alkyl, aryl, cycloalkyl, heterocyclo, and    heteroaryl, except when R₁₄ is joined to a sulphonyl group as in    —S(═O)R₁₄, —SO₂R₁₄, and —NR_(14a)SO₂R₁₄, then R₁₄ is not hydrogen;-   R₁₆ is selected from alkyl, R₁₇, and C₁₋₄alkyl substituted with keto    (═O) and/or one to three R₁₇;-   R₁₇ is selected from (a) halogen, haloalkyl, haloalkoxy, nitro,    cyano, —SR₂₃, —OR₂₃, —NR₂₃R₂₄, —NR₂₃SO₂R₂₅, —SO₂R₂₅, —SO₂NR₂₃R₂₄,    —CO₂R₂₃, —C(═O)R₂₃, —C(═O)NR₂₃R₂₄, —OC(═O)R₂₃, —OC(═O)NR₂₃R₂₄,    —NR₂₃C(═O)R₂₄, —NR₂₃CO₂R₂₄; (b) aryl or heteroaryl either of which    may be optionally substituted with one to three R₂₆; or (c)    cycloalkyl or heterocyclo, either of which may be optionally    substituted with one or more of keto (═O) and 1-3 R₂₆;-   R₁₈ and R₂₆ are independently selected from C₁₋₆alkyl, C₂₋₆alkenyl,    halogen, haloalkyl, haloalkoxy, cyano, nitro, amino, C₁₋₄alkylamino,    aminoC₁₋₄alkyl, hydroxy, hydroxyC₁₋₄alkyl, alkoxy, C₁₋₄alkylthio,    phenyl, benzyl, phenyloxy, and benzyloxy;-   R₁₉ is C₁₋₄alkyl, phenyl, C₃₋₇cycloalkyl, or 5-6 membered    heterocyclo or heteroaryl;-   R₂₀ and R₂₁ are each independently selected from the group    consisting of hydrogen, alkyl, alkenyl, substituted alkyl,    substituted alkenyl, phenyl, aryl, C₃₋₇cycloalkyl, and five-to-six    membered heterocyclo and heteroaryl;-   R₂₂ is selected from the group consisting of C₁₋₆alkyl, C₂₋₆alkenyl,    halogen haloalkyl, haloalkoxy, cyano, nitro; amino, C₁₋₄ alkylamino,    aminoC₁₋₄alkyl, hydroxy, hydroxyC₁₋₄ alkyl, alkoxy, alkylthio,    phenyl, benzyl, phenyloxy, and benzyloxy,-   R₂₃ and R₂₄ are each independently selected from hydrogen, alkyl,    alkenyl, substituted alkyl, substituted alkenyl, aryl, cycloalkyl,    heteroaryl, and heterocyclo;-   R₂₅ is selected from alkyl, substituted alkyl, aryl, heteroaryl,    cyclo alkyl and heterocyclo; and-   m is 0, 1, 2 or 3.

In one embodiment, the p38 kinase inhibitor from Genus IX is selectedfrom compounds 1-131 of U.S. Pat. No. 7,160,883.

In one embodiment, the p38 kinase inhibitor from Genus IX is selectedfrom the following:

In one embodiment, the p38 inhibitor is4-((5-(cyclopropylcarbamoyl)-2-methylphenyl)amino)-5-methyl-N-propylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide(“MBS-582949”), Formula IX′.

Genus IX Definitions

The term “alkyl” refers to straight or branched chain unsubstitutedhydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 7 carbonatoms. The expression “lower alkyl” refers to unsubstituted alkyl groupsof 1 to 4 carbon atoms. When a subscript is used with reference to analkyl or other group, the subscript refers to the number of carbon atomsthat the group may contain. For example, the term “C₀₋₄alkyl” includes abond and alkyl groups of 1 to 4 carbon atoms.

The term “substituted alkyl” refers to an alkyl group substituted by oneto four substituents selected from halogen, hydroxy, alkoxy, keto (═O),alkanoyl, aryloxy, alkanoyloxy, NR^(a)R^(b), alkanoylamino, aroylamino,aralkanoylamino, substituted alkanoylamino, substituted arylamino,substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio,alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl,aralkylsulfonyl, —SO₂NR^(a)R^(b), nitro, cyano, —CO₂H, —CONR^(a)R^(b),alkoxycarbonyl, aryl, guanidino and heteroaryls or heterocyclos (such asindolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl,pyrimidyl and the like), wherein R_(a) and R_(b) are selected fromhydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl,heteroarylalkyl, heterocycle, and heterocyclealkyl. The substituent onthe alkyl optionally in turn may be further substituted, in which caseit will be with substituted one or more of C₁₋₄alkyl, C₂₋₄alkenyl,halogen, haloalkyl, haloalkoxy, cyano, nitro, amino, C₁₋₄alkylamino,aminoC₁₋₄alkyl, hydroxy, hydroxyC₁₋₄alkyl, alkoxy, alkylthio, phenyl,benzyl, phenyloxy, and/or benzyloxy.

The term “alkenyl” refers to straight or branched chain hydrocarbongroups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, andmost preferably 2 to 8 carbon atoms, having at least one double bond,and depending on the number of carbon atoms, up to four double bonds.

The term “substituted alkenyl” refers to an alkenyl group substituted byone to two substituents selected from those recited above forsubstituted alkyl groups.

The term “alkynyl” refers to straight or branched chain hydrocarbongroups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, andmost preferably 2 to 8 carbon atoms, having at least one triple bond,and depending on the number of carbon atoms, up to four triple bonds.

The term “substituted alkynyl” refers to an alkynyl group substituted byone to two substituents selected from those recited above for alkylgroups.

When the term alkyl is used in connection with another group, as inheterocycloalkyl or cycloalkylalkyl, this means the identified (firstnamed) group is bonded directly through an alkyl group which may bebranched or straight chain (e.g., cyclopropylC1-4alkyl means acyclopropyl group bonded through a straight or branched chain alkylgroup having one to four carbon atoms.). In the case of substituents, asin “substituted cycloalkylalkyl,” the alkyl portion of the group,besides being branched or straight chain, may be substituted as recitedabove for substituted alkyl groups and/or the first named group (e.g.,cycloalkyl) may be substituted as recited herein for that group.

The term “halogen” or “halo” refers to fluorine, chlorine, bromine andiodine.

The term “aryl” refers to monocyclic or bicyclic aromatic substituted orunsubstituted hydrocarbon groups having 6 to 12 carbon atoms in the ringportion, such as phenyl, naphthyl, and biphenyl groups.) Aryl groups mayoptionally include one to three additional rings (either cycloalkyl,heterocyclo or heteroaryl) fused thereto. Examples include:

and the like. Each ring of the aryl may be optionally substituted withone to three Rc groups, wherein Rc at each occurrence is selected fromalkyl, substituted alkyl, halogen, trifluoromethoxy, trifluoromethyl,—SR, —OR, —NRR′, —NRSO2R′, —SO2R, —SO2NRR′, —CO2R′, —C(═O)R′,—C(═O)NRR′, —OC(═O)R′, —OC(═O)NRR′, —NRC(═O)R′, —NRCO2R′, phenyl, C₃₋₇cycloalkyl, and five-to-six membered heterocyclo or heteroaryl, whereineach R and R′ is selected from hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, phenyl, C₃₋₇cycloalkyl, and five-to-sixmembered heterocyclo or heteroaryl, except in the case of a sulfonylgroup, then R is not going to be hydrogen. Each substituent Rcoptionally in turn may be further substituted by one or more (preferably0 to 2) Rd groups, wherein Rd is selected from C1-6alkyl, C2-6alkenyl,halogen, haloalkyl, haloalkoxy, cyano, nitro, amino, C1-4alkylamino,aminoC1-4alkyl, hydroxy, hydroxyC1-4alkyl, alkoxy, alkylthio, phenyl,benzyl, phenylethyl, phenyloxy, and benzyloxy.

The term “aralkyl” refers to an aryl group bonded directly through analkyl group, such as benzyl, wherein the alkyl group may be branched orstraight chain. In the case of a “substituted aralkyl,” the alkylportion of the group besides being branched or straight chain, may besubstituted as recited above for substituted alkyl groups and/or thearyl portion may be substituted as recited herein for aryl. Thus, theterm “optionally substituted benzyl” refers to the group:

wherein each R group may be hydrogen or may also be selected from Rc asdefined above, in turn optionally substituted with one or more Rd. Atleast two of these “R” groups should be hydrogen and preferably at leastfive of the “R” groups is hydrogen. A preferred benzyl group involvesthe alkyl-portion being branched to define:

The term “heteroaryl” refers to a substituted or unsubstituted aromaticgroup for example, which is a 4 to 7 membered monocyclic, 7 to 11membered bicyclic, or 10 to 15 membered tricyclic ring system, which hasat least one heteroatom and at least one carbon atom-containing ring.Each ring of the heteroaryl group containing a heteroatom can containone or two oxygen or sulfur atoms and/or from one to four nitrogenatoms, provided that the total number of heteroatoms in each ring isfour or less and each ring has at least one carbon atom. The fused ringscompleting the bicyclic and tricyclic groups may contain only carbonatoms and may be saturated, partially saturated, or unsaturated. Thenitrogen and sulfur atoms may optionally be oxidized and the nitrogenatoms may optionally be quaternized. Heteroaryl groups which arebicyclic or tricyclic must include at least one fully aromatic ring butthe other fused ring or rings may be aromatic or non-aromatic. Theheteroaryl group may be attached at any available nitrogen or carbonatom of any ring. It may optionally be substituted with one to three(preferably 0 to 2) Rc groups, as defined above for aryl, which in turnmay be substituted with one or more (preferably o to 2) Rd groups, alsoas recited above.

Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl,pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl (i.e.,

thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like.

Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl,benzodioxolyl, benzoxaxolyl, benzothienyl, quinolinyl,tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl,cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl,dihydroisoindolyl, tetrahydroquinolinyl and the like.

Exemplary tricyclic heteroaryl groups include carbazolyl, benzidolyl,phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

The term “cycloalkyl” refers to a saturated or partially unsaturatednon-aromatic cyclic hydrocarbon ring system, preferably containing 1 to3 rings and 3 to 7 carbon atoms per ring, which may be substituted orunsubstituted and/or which may be fused with a C3-C7 carbocylic ring, aheterocyclic ring, or which may have a bridge of 3 to 4 carbon atoms.The cycloalkyl groups including any available carbon or nitrogen atomson any fused or bridged rings optionally may have 0 to 3 (preferably0-2) substituents selected from Rc groups, as recited above, and/or fromketo (where appropriate) which in turn may be substituted with one tothree Rd groups, also as recited above. Thus, when it is stated that acarbon-carbon bridge may be optionally substituted, it is meant that thecarbon atoms in the bridged ring optionally may be substituted with anRc group, which preferably is selected from C1-4alkyl, C2-4alkenyl,halogen, haloalkyl, haloalkoxy, cyano, amino, C1-4alkylamino,aminoC1-4alkyl, hydroxy, hydroxyC1-4alkyl, and C1-4alkoxy. Exemplarycycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, bicycloheptane, cycloctyl, cyclodecyl,cyclododecyl, and adamantyl.

The terms “heterocycle”, “heterocyclic” and “heterocyclo” each refer toa fully saturated or partially unsaturated nonaromatic cyclic group,which may be substituted or unsubstituted, for example, which is a 4 to7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 memberedtricyclic ring system, which has at least one heteroatom in at least onecarbon atom-containing ring. Each ring of the heterocyclic groupcontaining a heteroatom may have 1, 2 or 3 heteroatoms selected fromnitrogen, oxygen, and sulfur atoms, where the nitrogen and sulfurheteroatoms also optionally may be oxidized and the nitrogen heteroatomsalso optionally may be quaternized. Preferably two adjacent heteroatomsare not simultaneously selected from oxygen and nitrogen. Theheterocyclic group may be attached at any nitrogen or carbon atom. Theheterocyclo groups optionally may have 0 to 3 (preferably 0-2)substituents selected from keto (═O), and/or one or more Rc groups, asrecited above, which in turn may be substituted with one to three Rdgroups, also as recited above.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl,indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl,imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl,thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl,furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl,azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl,thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane andtetrahydro-1, 1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl,thiiranyl, triazinyl, and triazolyl, and the like.

Exemplary bicyclic hetrocyclic groups include2,3-dihydro-2-oxo-1H-indolyl, benzothiazolyl, benzoxazolyl,benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide,tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl,quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such asfuro[2,3-c]pyridinyl, furo[3,1-b]pyridinyl] or furo[2,3-b]pyridinyl),dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benzisoxazolyl,benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl,benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl,dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone,dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl,naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl,quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl,thienothienyl, and the like.

Also included are smaller heterocyclos, such as epoxides and aziridines.

Unless otherwise indicated, when reference is made to aspecifically-named aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl),heterocyclo (e.g., pyrrolidinyl) or heteroaryl (e.g., indolyl), thereference is intended to include rings having 0 to 3, preferably 0-2,substituents selected from those recited above for the aryl, cycloalkyl,heterocyclo and/or heteroaryl groups, as appropriate. Additionally, whenreference is made to a specific heteroaryl or heterocyclo group, thereference is intended to include those systems having the maximum numberof non-cumulative double bonds or less than the maximum number of doublebonds. Thus, for example, the term “isoquinoline” refers to isoquinolineand tetrahydroisoquinoline.

Additionally, it should be understood that one skilled in the field maymake appropriate selections for the substituents for the aryl,cycloalkyl, heterocyclo, and heteroaryl groups to provide stablecompounds and compounds useful as pharmaceutically-acceptable compoundsand/or intermediate compounds useful in makingpharmaceutically-acceptable compounds. Thus, for example, in compoundsof Formula (IX), when B is a cyclopropyl ring, preferably the ring hasno more than two substituents, and preferably said substituents do notcomprise nitro (NO₂), more than one cyano group, or three halogengroups. Similarly, when m is 3, preferably R₆, the substituents on thephenyl ring A, are not all nitro, and so forth.

The term “heteroatoms” shall include oxygen, sulfur and nitrogen.

The term “haloalkyl” means an alkyl having one or more halosubstituents.

The term “perfluoromethyl” means a methyl group substituted by one, two,or three fluoro atoms, i.e., CH₂F, CHF₂ and CF₃. The term“perfluoroalkyl” means an alkyl group having from one to five fluoroatoms, such as pentafluoroethyl.

The term “haloalkoxy” means an alkoxy group having one or more halosubstituents. For example, “haloalkoxy” includes —OCF₃.

The term “carbocyclic” means a saturated or unsaturated monocyclic orbicyclic ring in which all atoms of all rings are carbon. Thus, the termincludes cycloalkyl and aryl rings. The carbocyclic ring may besubstituted in which case the substituents are selected from thoserecited above for cycloalkyl and aryl groups.

When the term “unsaturated” is used herein to refer to a ring or group,the ring or group may be fully unsaturated or partially unsaturated.

Definitions for the various other groups that are recited above inconnection with substituted alkyl, substituted alkenyl, aryl,cycloalkyl, and so forth, are as follows: alkoxy is —OR_(e), alkanoyl is—C(═O)R_(e), aryloxy is —OAr, alkanoyloxy is —OC(═O)R_(e), amino is—NH₂, alkylamino is —NHR_(e) or —N(R_(e))₂, arylamino is —NHAr or—NR_(e)Ar, aralkylamino is —NH—R_(f)—Ar, alkanoylamino is—NH—C(═O)R_(e), aroylamino is —NH—C(═O)Ar, aralkanoylamino is—NH—C(═O)R_(f)—Ar, thiol is —SH, alkylthio is —SR_(e), arylthio is —SAr,aralkylthio is —S—R_(f)—Ar, alkylthiono is —S(═O)R_(e), arylthiono is—S(═O)Ar, aralkylthiono is —S(═O)R_(f)—Ar, alkylsulfonyl is —SO(q)R_(e),arylsulfonyl is —SO(q)Ar, arylsulfonylamine is —NHSO(q)Ar,alkylsulfonylamine is —NHSO₂R_(e), aralkylsulfonyl is —SO(q)R_(f)Ar,sulfonamido is —SO₂NH₂, substituted sulfonamide is —SO₂NHR_(e) or—SO₂N(R_(e))₂, nitro is —NO₂, carboxy is —CO₂H, carbamyl is —CONH₂,substituted carbamyl is —C(═O)NHR_(g) or —C(═O)NR_(g)R_(h),alkoxycarbonyl is —C(═O)OR_(e), carboxyalkyl is —R_(f)—CO₂H sulfonicacid is —SO₃H, guanidino is

and ureido is

wherein R_(e) is alkyl or substituted alkyl as defined above, R_(f) isalkylene or substituted alkylene as defined above, R_(g) and R_(h) areselected from alkyl, substituted alkyl, aryl, aralkyl, cycloalkyl,heterocyclo, and heteraryl; Ar is an aryl as defined above, and q is 2or 3.

Genus X Description

Compounds of Genus X can be prepared according to the disclosure of US2005-0176775, which is herein incorporated herein by reference in itsentirety.

Genus X is characterized by compounds of Formula X:

or stereoisomers thereof, isotopically-enriched compounds thereof,prodrugs thereof, solvates thereof, and pharmaceutically acceptablesalts thereof;wherein:

-   R₁ is halogen substituted with 1, 2, 3, 4, or 5 groups that are    independently halogen, —(C₁-C₆)alkyl-N(R)CO₂R₃₀, haloalkyl,    heteroaryl, heteroarylalkyl, —NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-,    —C(O)NR₆R₇, —(C₁-C₄)alkyl-C(O)NR₆R₇, —(C₁-C₄ alkyl)-NRC(O)NR₁₆R₁₇,    haloalkoxy, alkyl, —CN, hydroxyalkyl, dihydroxyalkyl, alkoxy,    alkoxycarbonyl, phenyl, —SO₂-phenyl wherein the phenyl and    —SO₂-phenyl groups are optionally substituted with 1, 2, or 3 groups    that are independently halogen or —NO₂, or —OC(O)NR₆R₇,    -   wherein:        -   R₁₆ and R₁₇ are independently H or C₁-C₆ alkyl, or        -   R₁₆, R₁₇ and the nitrogen to which they are attached form a            morpholinyl ring;            -   R₆ and R₇ are independently at each occurrence —H,                alkyl, hydroxyalkyl, dihydroxyalkyl, alkoxy, alkanoyl,                arylalkyl, arylalkoxy, alkoxycarbonyl, —SO2-alkyl, —OH,                alkoxy, alkoxyalkyl, arylalkoxycarbonyl,                —(C₁-C₄)alkyl-CO₂-alkyl, heteroarylalkyl, or                arylalkanoyl,                -   wherein each is unsubstituted or substituted with 1,                    2, or 3 groups that are independently, halogen, —OH,                    —SH, heterocycloalkyl, heterocycloalkylalkyl, C₃-C₇                    cycloalkyl, alkoxy, —NH₂, —NH(alkyl),                    N(alkyl)(alkyl), —O-alkanoyl, alkyl, haloalkyl,                    carboxaldehyde, or haloalkoxy, or            -   R₆, R₇, and the nitrogen to which they are attached form                a morpholinyl, pyrrolidinyl, thiomorpholinyl,                thiomorpholinyl-S-oxide, thiomorpholinyl S,S-dioxide,                piperidinyl, pyrrolidinyl, or piperazinyl ring which is                optionally substituted with 1 or 2 groups that are                independently C₁-C₄ alkyl, alkoxycarbonyl, C₁-C₄ alkoxy,                hydroxyl, hydroxyalkyl, dihydroxyalkyl, or halogen;        -   R₃₀ is C₁-C₆ alkyl optionally substituted with 1 or 2 groups            that are independently —OH, —SH, halogen, amino,            monoalkylamino, dialkylamino or C₃-C₆ cycloalkyl;-   R₃ is —H, halogen, alkoxycarbonyl, arylalkoxycarbonyl,    aryloxycarbonyl, arylalkyl, —OC(O)NH(CH₂)_(n)aryl, arylalkoxy,    —OC(O)N(alkyl)(CH₂)_(n)aryl, aryloxy, arylthio, thioalkoxy,    arylthioalkoxy, alkenyl, —NR₆R₇, NR₆R₇—(C₁-C₆)alkyl, or alkyl,    -   wherein:        -   the aryl portion of arylalkoxycarbonyl, aryloxycarbonyl,            arylalkyl, —OC(O)NH(CH₂)_(n)aryl, arylalkoxy,            —OC(O)N(alkyl)(CH₂)_(n)aryl, and arylthioalkoxy, is            unsubstituted or substituted with 1, 2, 3, 4, or 5 groups            that are independently, halogen, alkoxy, alkyl, haloalkyl,            or haloalkoxy,            -   wherein:                -   n is 0, 1, 2, 3, 4, 5, or 6;-   R₄ is alkyl unsubstituted or substituted with one or two groups that    are independently —CO₂R, —CO₂—(C₁-C₆)alkyl, —C(O)NR₆R₇, —C(O)R₆,    —N(R₃₀)C(O)NR₁₆R₁₇, —N(R₃₀)C(O)—(C₁-C₆)alkoxy, or —NR₆R₇,    arylalkoxy, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyalkyl,    dihydroxyalkyl, haloalkyl, R₆R₇N—(C₁-C₆—NR₆R₇, alkoxy,    carboxaldehyde, —C(O)NR₆R₇, CO₂R, alkoxyalkyl, or alkoxyalkoxy,    wherein the heteroaryl or aryl portions of is the above are    unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are    independently halogen, hydroxy, alkoxy, alkyl, —CO₂—(C₁-C₆)alkyl,    —CONR₆R₇, —NR₆R₇, R₆R₇N—(C₁-C₆)alkyl-, nitro, haloalkyl, or    haloalkoxy; and-   R₅ is H, aryl, arylalkyl, arylthioalkyl, alkyl optionally    substituted with 1, 2, or 3 groups that are independently    arylalkoxycarbonyl, —NR₈R₉, halogen, —C(O)NR₈R₉, alkoxycarbonyl,    C₃-C₇ cycloalkyl, or alkanoyl, alkoxy, alkoxyalkyl optionally    substituted with one trimethylsilyl group, amino, alkoxycarbonyl,    hydroxyalkyl, dihydroxyalkyl, —SO₂-alkynyl, alkoxy optionally    substituted with one trimethylsilyl group, heterocycloalkylalkyl,    cycloalkyl, cycloalkylalkyl, -alkyl-S-aryl, -alkyl-SO₂-aryl,    heteroarylalkyl, heterocycloalkyl, heteroaryl, or alkenyl optionally    substituted with alkoxycarbonyl,    -   wherein:        -   each of the above is unsubstituted or substituted with 1, 2,            3, 4, or 5 groups that are independently alkyl, halogen,            alkoxy, hydroxyalkyl, dihydroxyalkyl, arylalkoxy,            thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl, CO₂R, CN,            OH, hydroxyalkyl, dihydroxyalkyl, amidinooxime, —NR₆R₇,            —NR₈R₉, R₆R₇N—(C₁-C₆alkyl)-, carboxaldehyde, SO₂ alkyl,            —SO₂H, —SO₂NR₆R₇, alkanoyl wherein the alkyl portion is            optionally substituted with OH, halogen or alkoxy,            —C(O)NR₆R₇, —(C₁-C₄alkyl)-C(O)NR₆R₇, amidino, haloalkyl,            —(C₁-C₄alkyl)-NR₁₅C(O)NR₁₆R₁₇, —(C₁-C₄alkyl)-NR₁₅C(O)R₁₈,            —O—CH₂O, —O—CH₂CH₂O—, or haloalkoxy; wherein:            -   R₁₅ is H or C₁-C₆ alkyl; and            -   R₁₈ is C₁-C₆ alkyl optionally substituted with —O(C₂-C₆                alkanoyl, C₁-C₆hydroxyalkyl, C₁-C₆ dihydroxyalkyl, C₁-C₆                alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl; amino C₁-C₆ alkyl,                mono or dialkylamino C₁-C₆ alkyl.-   3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-1-(1H-pyrazol-4-ylmethyl-1H-pyridin-2-one;-   2-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-methyl}benzonitrile;-   3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-methyl}benzonitrile;-   4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-methyl}benzonitrile;-   4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-methyl}benzamide;-   Methyl    4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-methyl}benzate;-   Methyl    3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-methyl}benzate;-   3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-methyl}benzamide;-   2-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-methyl}benzamide;-   1-[2-(aminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-1(2H)-yl-one;-   3-bromo-1-[3-(bromomethyl)benzyl]-4[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-bromo-1-[4-(bromomethyl)benzyl]-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[4-(aminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[3-(aminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[3-((morpholin-4-yl)methyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[3-((dimethylamino)methyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[3-((isopropylamino)methyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[3-((piperidin-1-yl)methyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[3-((2-hydroxyethyl)amino)methyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[3-((bis(2-hydroxyethyl)amino)methyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[3-((piperazin-1-yl)methyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}benzoic acid;-   1-[3-((1-oxoethyl)aminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[3-(carbomethoxyaminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[3-(methylsulfonylaminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[3-(glycolylaminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[3-(aminocarbonylaminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[4-(isopropylaminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[4-(morpholin-4-ylmethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[4-(dimethylaminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[4-(piperidin-1-ylmethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[4([bis(2-hydroxyethyl)amino]methyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[4-((2-etholyl)aminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[4-piperazin-1-ylmethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[4-(methoxycarbonylaminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[4-(acetylaminomethylbenzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[4-(methylsulfonylaminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[4-(carbamylaminomethyl)benzyl]-3-bromo-4-[(2,4-diflorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   4-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}benzoyl)piperazine-1-carboxamide;-   N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}benzyl)-2-methoxyacetamide;-   methyl    2-(4-((4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)methyl)benzylcarbamoyl)acetate;-   N-(4-((4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)methyl)benzyl)-2-hydroxy-2-methylpropanamide;-   N-(4-((4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)methyl)benzyl)-1-hydroxycyclopropanecarboxamide;-   N-(4-((4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)methyl)benzyl)-2-aminoacetamide;-   N-(4-((4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)methyl)benzyl)-2-hydroxyacetamide;-   N-(4-((4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)methyl)benzyl)-2-(1-oxoethylamino)acetamide;-   1-{4-[(4-acetylpiperazin-1-yl)carbonyl]benzyl}-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(4-{[4-(methylsulfonyl)piperazin-1-yl]carbonyl}benzyl)pyridin-2(1H)-one;-   3-Bromo-4-[(2,4-diflurobenzyl)oxy]-1-[3-(hydroxymethyl)phenyl]-6-methylpyridin-2(1H)-one;-   Methyl-4-[3-bromo-4-[(difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1-(2H)-yl]benzoate;-   4-[3-bromo-4-[(difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoic    acid;-   4-(Benzyloxy)-1-(3-fluorobenzyl)-3-(trifluoromethyl)pyridin-2(1H)-one;-   4-{[3-bromo-4-[(2,4-difluorobenzyloxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}benzoic acid;-   3-Bromo-4-[(2,4-diflurobenzyl)oxy]-1-[4-(hydroxymethyl)benzyl]-6-methylpyridin-2(1H)-one;-   3-Bromo-4-[(2,4-diflurobenzyl)oxy]-1-[4-(1-hydroxy-1-methylethyl)benzyl]-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-diflurobenzyl)oxy]-6-methyl-1-{4-[(methylamino)methyl]benzyl}pyridin-2(1H)-one;-   4-[(2,4-diflurobenzyl)oxy]-1-(4-methoxybenzyl)-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-diflurobenzyl)oxy]-1-(4-methoxybenzyl)-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-diflurobenzyl)oxy]-1-(4-hydroxybenzyl)-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1    {4-[(4-hydroxy-4-methylpiperidin-1-yl)carbonyl]benzyl}-6-methylpyridin-2(1H)-one;-   4-{[3-bromo-4-[(2,4-difluorobenzyloxy]-6-methyl-2-oxypyridin-1    (2H)-yl]methyl}-N-(2-hydroxy-2-methylpropyl)benzamide;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1    {4-[(4-hydroxypiperidin-1-yl)carbonyl]benzyl}-6-methylpyridin-2(1H)-one;-   4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}-N-(2-hydroxyethyl)benzamide;-   3-bromo-4-(2,4-difluorophenoxy)-6-methyl-1-[4-((aminoethyl)aminocarbonyl)benzyl]pyridin-2(1H)-one;-   3-bromo-4-(2,4-difluorophenoxy)-6-methyl-1-[4-((aminopropyl)aminocarbonyl)benzyl]pyridin-2(1H)-one;-   3-bromo-4-(2,4-difluorophenoxy)-6-methyl-1-[4-(hydroxyaminocarbonyl)benzyl]pyridin-2(1H)-one;-   3-bromo-4-(2,4-difluorophenoxy)-6-methyl-1-[4-((aminomethyl)aminocarbonyl)benzyl]pyridin-2(1H)-one;-   3-bromo-4-(2,4-difluorophenoxy)-6-methyl-1-[4-(dimethylaminocarbonyl)benzyl]pyridin-2(1H)-one;-   3-bromo-4-(2,4-difluorophenoxy)-6-methyl-1-[4-(diethanol-2-ylaminocarbonyl)benzyl]pyridin-2(1H)-one;-   3-bromo-4-(2,4-difluorophenoxy)-6-methyl-1-[4-(isoyropylaminocarbonyl)benzyl]pyridin-2(1H)-one;-   3-bromo-4-(2,4-difluorophenoxy)-6-methyl-1-[4-((dimethylaminoethyl)aminocarbonyl)benzyl]pyridin-2(1H)-one;-   3-bromo-4-(2,4-difluorophenoxy)-6-methyl-1-[4-((methoxyethyl)aminocarbonyl)benzyl]pyridin-2(1H)-one;-   3-bromo-4-(2,4-difluorophenoxy)-6-methyl-1-[4-((ethanol-2-yl)methylaminocarbonyl)benzyl]pyridin-2(1H)-one;-   3-bromo-4-(2,4-difluorophenoxy)-6-methyl-1-[4-((methoxyethyl)methylaminocarbonyl)benzyl]pyridin-2(1H)-one;-   4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-N-(2-hydroxyethyl)benzamide;-   4-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-N-(2-aminoethyl)benzamide;-   4-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-N-(3-aminopropyl)benzamide;-   4-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-N-hydroxybenzamide;-   4-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-N-methylbenzamide;-   4-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-N,N-dimethylbenzamide;-   4-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-N,N-bis(2-hydroxyethyl)benzamide;-   4-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-N-isopropylbenzamide;-   4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzamide;-   Methyl-4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}benzoate;-   3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}-N-methylbenzamide;-   3-((4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)methyl)-N-(2-aminoethyl)benzamide;-   3-((4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)methyl)-N-(3-aminopropyl)benzamide;-   3-((4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)methyl)-N-hydroxybenzamide;-   3-((4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)methyl)-N,N-dimethylbenzamide;-   3-((4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)methyl)-N-(2-hydroxyethyl)benzamide;-   3-((4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)methyl)-N,N-bis(2-hydroxyethyl)benzamide;-   3-((4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)methyl)-N-isopropylbenzamide;-   N-(3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl)methyl}benzyl]-2-methoxyacetamide;-   N-(3-((4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)methyl)benzyl)-2-aminoacetamide;-   N-(3-((4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)methyl)benzyl)-2-(1-oxoethylamino)acetamide;-   N-(3-((4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)methyl)benzyl)-3-oxobutanamide;-   N-(3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl})benzyl)-2-hydroxy-2-methylpropanamide;-   N-(3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}benzyl)-1-hydroxycyclopropanecarboxamide;-   N′-(3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}benzyl)-N,N-dimethylurea;-   1-(3-((4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)methyl)benzyl)-3-methylurea;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]benzoic acid;-   Ethyl    3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-N-methylbenzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-N-(2-aminoethyl)benzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-N-(3-aminopropyl)benzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-N-hydroxybenzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-N,N-dimethylbenzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-N-(2-hydroxyethyl)benzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-N-isopropylbenzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-N-(2-(dimethylamino)ethyl)-benzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-N-(2-methoxyethyl)benzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-N-(2-(dimethylamino)ethyl)-N-methylbenzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-N-(2-hydroxyethyl)-N-methylbenzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-N-(2-methoxyethyl)-N-methylbenzamide;    3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]benzamide;-   3-[3-chloro-4-[(2,4-difluorobenzy)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]benzoic acid;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[3-(hydroxymethyl)phenyl]-6-methylpyridin-2(1H)-one;-   1-[3-(aminomethyl)phenyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]benzyl}methanesulfonamide;-   N-(3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)benzyl)acetamide;-   methyl    3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)benzylcarbamate;-   N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]benzyl}-2-methoxyacetamide;-   N-(3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)benzyl)-2-aminoacetamide;-   N-(3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)benzyl)-2-hydroxyacetamide;-   N′-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]benzyl}-N,N-dimethylurea;-   1-(3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)benzyl)-3-methylurea;-   N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]benzyl}urea;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-{3-[(dimethylamino)methyl]phenyl}-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyloxy]-6-methyl-1-(2-morpholin-4-ylethyl)pyridin-2(1H)-one;-   3-bromo-1-(4-bromo-2,6-difluorophenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(2,4,6-trifluorophenyl)pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(2,4,6-trifluorophenyl)pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-1-(2,4,6-trifluorophenyl)pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-1-(2,4,6-trifluorophenyl)pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluoro-4-morpholin-4-ylphenyl)-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[2,6-difluoro-4-(4-methylpiperazin-1-yl)phenyl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[2,6-difluoro-4-(4-methylpiperazin-1-yl)phenyl]-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[4-(dimethylamino)-2,6-difluorophenyl]-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-{2,6-difluoro-4-[(2-hydroxyethyl)(methyl)amino]phenyl}-6-methylpyridin-2(1H)-one;-   3-bromo-1-(3,5-dibromo-2,6-difluoro-4-hydroxyobenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   2-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3,5-difluorophenoxyl}acetamide;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[2,6-difluoro-4-(2-hydroxyethoxy)phenyl]-6-methypyridin-2(1H)-one;-   3-bromo-1-(2,6-difluorophenyl)-4-{[4-fluoro-2-(hydroxymethyl)benzyl]oxy}-6-methylpyridin-2(1H)-one;-   3-chloro-1-(2,6-difluorophenyl)-4-{[4-fluoro-2-(hydroxymethyl)benzyl]oxy}-6-methylpyridin-2(1H)-one;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-2-methyl)-N-(2-morpholin-4-ylethyl)benzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-N-(2-methoxyethyl)-2-methylbenzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-N,N,2-trimethylbenzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-N-(2-hydroxyethyl)-2-methylbenzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-N,2-dimethylbenzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-N-(2-hydroxyethyl)-N,2-dimethylbenzamide;-   4-(2,4-difluorobenzyloxy)-1-(3-(4-methylpiperazin-1-yl)carbonyl-2-methylphenyl)-3-bromo-6-methylpyridin-2(1H)-one;-   4-(2,4-difluorobenzyloxy)-1-(3-(morpholin-4-yl)carbonyl-2-methylphenyl)-3-bromo-6-methylpyridin-2(1H)-one;-   3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-N-(2-methoxyethyl)-N,2-dimethylbenzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-2-methylbenzamide;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[3-(hydroxymethyl)-2-methylphenyl]-6-methylpyridin-2(1H)-one;-   3-[3-chloro-4-[(2,4-difluorobenzyhoxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N-(2-methoxyethyl)-2-methylbenzamide;-   3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N,2-dimethylbenzamide;-   3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N-(2-hydroxyethyl)-2-methylbenzamide;-   3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-2-methylbenzamide;-   3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-dimethylphenyl)-6-methylpyridin-2(1H)-one;-   3-Bromo-1-(2,6-dimethylphenyl)-4-[(4-fluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-Bromo-1-(2,6-dimethylphenyl)-6-methyl-4-[(2,4,6-trifluorobenzyl)oxy]pyridin-2(1H)-one;-   3-Bromo-4-[(2,6-difluorobenzyl)oxy]-1-(2,6-dimethylphenyl)-6-methylpyridin-2(1H)-one;-   3-Bromo-1-(2,6-dichlorophenyl)-4-[(4-fluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-Bromo-1-(2,6-dichlorophenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-Bromo-1-(2,6-dichlorophenyl)-4-[(2,6-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2-methoxy-6-methylphenyl)-6-methylpyridin-2(1H)-one;-   4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3,5-dichlorobenzenesulfonamide;-   3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one;-   3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2(1H)-one;-   3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-[2-(dimethylamino)-4,6-difluorophenyl]-6-methylpyridin-2(1H)-one;-   3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-{2,4-difluoro-6-[(2-hydroxyethyl)(methyl)amino]phenyl}-6-methylpyridin-2(1H)-one;-   2-({[3-Bromo-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzonitrile;-   4-{[2-(Aminomethyl)-4-fluorobenzyl]oxy}-3-bromo-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one    trifluoroacetate;-   N-[2-({[3-bromo-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzyl]urea;-   Methyl    2-({[3-bromo-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzylcarbamate;-   N-[2-({[3-bromo-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzyl]-2-hydroxyacetamide;-   Ethyl    2-({[3-chloro-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzylcarbamate;-   Isobutyl    2-({[3-chloro-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzylcarbamate;-   Cycloyronylmethyl    2-({[3-chloro-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzylcarbamate;-   1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one    trifluoroacetate;-   1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one    hydrochloride;-   1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one    trifluoroacetate;-   1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one    hydrochloride;-   3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-(1H-indazol-5-ylmethyl)-6-methylpyridin-2(1H)-one    trifluoroacetate;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-{[2-(methylthio)pyrimidin-4-yl]methyl}pyridin-2(1H)-one;-   3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-{[2-(methyl    sulfonyl)pyrimidin-4-yl]methyl}pyridin-2(1H)-one;-   4-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}pyrimidine-2-carbonitrile trifluoroacetate;-   4-{[2-(Aminomethyl)-4-fluorobenzyl]oxy}-3-bromo-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one    trifluoroacetate;-   3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-[(2-methoxypyrimidin-4-yl)methyl]-6-methylpyridin-2(1H)-one    trifluoroacetate;-   Methyl    4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrimidine-2-carboxylate    trifluoroacetate;-   3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-[(2-hydroxypyrimidin-4-yl)methyl]-6-methylpyridin-2(1H)-one    trifluoroacetate;-   4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}pyrimidine-2-carboxamide trifluoroacetate;-   Methyl    (4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrimidin-2-yl)methylcarbamate;-   3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[(5-methylpyrazin-2-yl)methyl]pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyrazin-2-ylmethyl)pyridin-2(1H)-one;-   3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-{[5-(hydroxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(1H)-one;-   3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-{5-[(dimethylamino)methyl]pyrazin-2-yl}methyl)-6-methylpyridin-2(1H)-one    trifluoroacetate;-   3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-[(5-{[(2-hydroxyethyl)-(methyl)amino]methyl}pyrazin-2-yl)methyl]-6-methylpyridin-2(1H)-one    trifluoroacetate;-   3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-({5-[(4-methylpiperazin-1-yl)carbonyl]pyrazin-2-yl}methyl)pyridin-2(1H)-one    trifluoroacetate;-   3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-({5-[(4-methylpiperazin-1-yl)carbonyl]pyrazin-2-yl}methyl)pyridin-2(1H)-one;-   5-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}-N-(2-hydroxyethyl)-N-methylpyrazine-2-carboxamide;-   5-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}-N-(2,3-dihydroxypropyl)pyrazine-2-carboxamide;-   5-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}-N-(2-hydroxyethyl)pyrazine-2-carboxamide;-   3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-{[5-(methoxymethyl)pyrazin-2-yl]methyl})-6-methylpyridin-2(1H)-one;-   3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-({5-[(2-methoxyethoxy)methyl]pyrazin-2-yl}methyl)-6-methylpyridin-2(1H)-one;-   (5-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}pyrazin-2-yl)methyl carbamate;-   1-benzyl-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one;-   3-bromo-1-(4-fluorobenzyl)-4-[(4-fluorobenzyl)amino]-6-methylpyridin-2(1H)-one;-   3-bromo-1-(cyclpyropylmethyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one;-   4-(4-fluorobenzyloxy)-3-bromo-6-methyl-1-((pyridin-4-yl)methyl)pyridin-2(1H)-one;-   4-(2,4,6-trifluorobenzyloxy)-3-bromo-6-methyl-1-((pyridin-4-yl)methyl)pyridin-2(1H)-one;-   4-(2,6-difluorobenzyloxy)-3-bromo-6-methyl-1-((pyridin-4-yl)methyl)pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;-   4-(4-fluorobenzyloxy)-3-bromo-6-methyl-1-((pyridin-3-yl)methyl)pyridin-2(1H)-one;-   4-(2,4,6-trifluorobenzyloxy)-3-bromo-6-methyl-1-(pyridin-3-yl)methyl)pyridin-2(1H)-one;-   4-(2-fluorobenzyloxy)-3-bromo-6-methyl-1-((pyridin-3-yl)methyl)pyridin-2(1H)-one;-   4-(2,4,5-trifluorobenzyloxy)-3-bromo-6-methyl-1-((pyridin-3-ylmethyl)pyridin-2(1H)-one;-   4-(4-chloro-2-fluorobenzyloxy)-3-bromo-6-methyl-1-((pyridin-3-yl)methyl)pyridin-2(1H)-one;-   4-(2-chloro-4-fluorobenzyloxy)-3-bromo-6-methyl-1-((pyridin-3-yl)methyl)pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-2-ylmethyl)pyridin-2(1H)-one;-   4-(2,6-difluorobenzyloxy)-3-bromo-6-methyl-1-((pyridin-3-yl)methyl)pyridin-2(1H)-one;-   4-(4-fluorobenzyloxy)-3-bromo-6-methyl-1-((pyridin-2-yl)methyl)pyridin-2(1H)-one;-   4-(2,4,6-trifluorobenzyloxy)-3-bromo-6-methyl-1-((pyridin-2-yl)methyl)pyridin-2(1H)-one;-   4-(2,4,5-trifluorobenzyloxy)-3-bromo-6-methyl-1-((pyridin-2-yl)methyl)pyridin-2(1H)-one;-   3-bromo-4-[2-(4-fluorophenyl)ethyl]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;-   3-bromo-4-[2-(4-fluorophenyl)ethyl]-6-methyl-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;-   1-[(4-amino-2-methylpyrimidin-5-ylmethyl]-3-bromo-6-methyl-4-[(2,4,6-trifluorobenzyl)oxy]pyridin-2(1H)-one    trifluoroacetate;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-{[2-methyl-4-(methylamino)pyrimidin-5-yl]methyl}pyridin-2(1H)-one    trifluoroacetate;-   ethyl    N-(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl)}-2-methylpyrimidin-4-yl)glycinate    trifluoroacetate;-   N-(5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl)}-2-methylpyrimidin-4-yl)-2-hydroxyacetamide    trifluoroacetate;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-({5-[(4-hydroxypiperidin-1-yl)carbonyl]pyrazin-2-yl}methyl)-6-methylpyridin-2(1H)-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}-N-(3-hydroxy-2,2-dimethylpropyl)pyrazine-2-carboxamide;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}-N-(2,2,2-trifluoroethyl-pyrazine-2-carboxamide;-   1-allyl-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-allyl-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   Methyl    (2E)-4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]but-2-enoate;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-prop-2-ynylpyridin-2(1H)-one;-   3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-[(dimethylamino)methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-(hydroxymethyl)pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-(hydroxymethyl)pyridin-2(1H)-one;-   5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridine-2-carbaldehyde;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-[(dimethylamino)methyl]pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-(morpholin-4-ylmethyl)pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-{[(2-methoxyethyl)amino]methyl}pyridin-2(1H)-one;-   5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridine-2-carboxylic    acid;-   Methyl    4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-methylbenzoate;-   4-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-3-methylbenzoic acid;-   4-(2,4-difluorobenzyloxy)-3-bromo-1-(4-(hydroxymethyl)-2-methylphenyl)-6-methylpyridin-2(1H)-one;-   4-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-N-(2-methoxyethyl)-3-methylbenzamide;-   4-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-N,3-dimethylbenzamide;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(2-methyl-4-vinylphenyl)pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[4-(1,2-dihydroxyethyl)-2-methylphenyl]-6-methylpyridin-2(1H)-one;-   methyl    3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-chlorobenzoate;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-4-chlorobenzoic acid;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[5-(hydroxymethyl)-2-methylphenyl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[5-(hydroxymethyl)-2-methylphenyl]-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-{5-[(dimethylamino)methyl]-2-methylphenyl}-6-methylpyridin-2(1H)-one    hydrochloride;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-{5-[(isopropylamino)methyl]-2-methylphenyl}-6-methylpyridin-2(1H)-one    hydrochloride;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-N-(2-hydroxyethyl)-4-methylbenzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-N-(2-methoxyethyl)-4-methylbenzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-N,4-dimethylbenzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-N,N,4-trimethylbenzamide;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[5-(1-hydroxy-1-methylethyl)-2-methylphenyl]-6-methylpyridin-2(1H)-one;-   methyl    3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoate;-   methyl    4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-chlorobenzoate;-   3-bromo-4-[(2,4-difluorobenzyl)amino]-6-methyl-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)amino]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)amino]-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)amino]-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one;-   3-{[3-chloro-4-[(2,4-difluorobenzyl)amino]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}benzonitrile;-   4-{[3-chloro-4-[(2,4-difluorobenzyl)amino]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}benzonitrile;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[2-fluoro-5-(hydroxymethyl)phenyl]-6-methylpyridin-2(1H)-one;-   3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoic    acid;-   3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluoro-N-methylbenzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-chloro-6-methyl-2-oxopyridin-1(2H)-yl)-4-fluoro-N,N-dimethylbenzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-chloro-6-methyl-2-oxopyridin-1(2H)-yl)-4-fluoro-N-(2-hydroxyethyl)benzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-chloro-6-methyl-2-oxopyridin-1(2H)-yl)-4-fluoro-N-(2-methoxyethyl)benzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-chloro-6-methyl-2-oxopyridin-1(2H)-yl)-4-fluoro-N-(2-hydroxyethyl)-N-methylbenzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-chloro-6-methyl-2-oxopyridin-1(2H)-yl)-4-fluoro-N-(3-hydroxypropyl)benzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-chloro-6-methyl-2-oxopyridin-1(2H)-yl)-4-fluoro-N-(2,3-dihydroxypropyl)benzamide;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-4-fluorobenzoic acid;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-4-methoxybenzoic acid;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-4-methoxy-N-methylbenzamide;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-4-methoxy-N,N-dimethylbenzamide;-   1-[(5-aminomethyl)-2-fluorophenyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one    hydrochloride;-   3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluoro-N-[2-hydroxy-1-(hydroxymethyl)ethyl]benzamide;-   N-(3-(4-(2,4-difluorobenzyloxy)-3-chloro-6-methyl-2-oxopyridin-1    (2H)-yl)-4-fluorobenzyl)acetamide;-   N-(3-(4-(2,4-difluorobenzyloxy)-3-chloro-6-methyl-2-oxopyridin-1    (2H)-yl)-4-fluorobenzyl)-2-methoxyacetamide;-   N-(3-(4-(2,4-difluorobenzyloxy)-3-chloro-6-methyl-2-oxopyridin-1    (2H)-yl)-4-fluorobenzyl)-methylsulfonamine;-   1-(3-(4-(2,4-difluorobenzyloxy)-3-chloro-6-methyl-2-oxopyridin-1    (2H)-yl)-4-fluorobenzyl)urea;-   2-({[3-chloro-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzonitrile;-   4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-3-chloro-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one    trifluoroacetate;-   methyl    2-((3-chloro-1-(2,6-difluorophenyl)-1,2-dihydro-6-methyl-2-oxopyridin-4-yloxy)methyl)-5-fluorobenzylcarbamate;-   N-(2-((3-chloro-1-(2,6-difluorophenyl)-1,2-dihydro-6-methyl-2-oxopyridin-4-yloxy)methyl)-5-fluorobenzyl)-2,2,2-trifluoroacetamide;-   isopropyl    2-((3-chloro-1-(2,6-difluorophenyl)-1,2-dihydro-6-methyl-2-oxopyridin-4-yloxy)methyl)-5-fluorobenzylcarbamate;-   1-(2-((3-chloro-1-(2,6-difluorophenyl)-1,2-dihydro-6-methyl-2-oxopyridin-4-yloxy)methyl)-5-fluorobenzyl)-3-ethylurea;-   tetrahydrofuran-3-yl    2-((3-chloro-1-(2,6-difluorophenyl)-1,2-dihydro-6-methyl-2-oxopyridin-4-yloxy)methyl)-5-fluorobenzylcarbamate;-   propyl    2-((3-chloro-1-(2,6-difluorophenyl)-1,2-dihydro-6-methyl-2-oxopyridin-4-yloxy)methyl)-5-fluorobenzylcarbamate;-   allyl    2-((3-chloro-1-(2,6-difluorophenyl)-1,2-dihydro-6-methyl-2-oxopyridin-4-yloxy)methyl)-5-fluorobenzylcarbamate;-   prop-2-ynyl    2-((3-chloro-1-(2,6-difluorophenyl)-1,2-dihydro-6-methyl-2-oxopyridin-4-yloxy)methyl)-5-fluorobenzylcarbamate;

or pharmaceutically acceptable salts thereof.

40. A compound of claim 1 which is

-   t-butyl    2-((3-chloro-1-(2,6-difluorophenyl)-1,2-dihydro-6-methyl-2-oxopyridin-4-yloxy)methyl)-5-fluorobenzylcarbamate;-   1-(2-((3-chloro-1-(2,6-difluorophenyl)-1,2-dihydro-6-methyl-2-oxopyridin-4-yloxy)methyl)-5-fluorobenzyl)-3-tert-butylurea;-   N-(2-((3-chloro-1-(2,6-difluoroyhenyl)-1,2-dihydro-6-methyl-2-oxopyridin-4-yloxy)methyl)-5-fluorobenzyl)-2-(propylsulfonyl)acetamide;-   N-(2-((3-chloro-1-(2,6-difluorophenyl)-1,2-dihydro-6-methyl-2-oxopyridin-4-yloxy)methyl)-5-fluorobenzyl)-2-(ethylsulfonyl)acetamide;-   1-(2-((3-chloro-1-(2,6-difluorophenyl)-1,2-dihydro-6-methyl-2-oxopyridin-4-yloxy)methyl)-5-fluorobenzyl)-3-isopropylurea-   1-(2-((3-chloro-1-(2,6-difluorophenyl)-1,2-dihydro-6-methyl-2-oxopyridin-4-yloxy)methyl)-5-fluorobenzyl)-3-methylurea;-   3-(2-((3-chloro-1-(2,6-difluorophenyl)-1,2-dihydro-6-methyl-2-oxopyridin-4-yloxy)methyl)-5-fluorobenzyl)-1-tert-butyl-1-methylurea;-   1-(2-((3-chloro-1-(2,6-difluorophenyl)-1,2-dihydro-6-methyl-2-oxopyridin-4-yloxy)methyl)-5-fluorobenzyl)-3-cyclpyropylurea;-   1-(2-((3-chloro-1-(2,6-difluorophenyl)-1,2-dihydro-6-methyl-2-oxopyridin-4-yloxy)methyl)-5-fluorobenzyl)-3-(2,2,2-trifluoroethyl)urea;-   1-(2-((3-chloro-1-(2,6-difluorophenyl)-1,2-dihydro-6-methyl-2-oxopyridin-4-yloxy)methyl)-5-fluorobenzyl)-3-(cyclopropylmethyl)urea;-   1-(2-((3-chloro-1-(2,6-difluorophenyl)-1,2-dihydro-6-methyl-2-oxopyridin-4-yloxy)methyl)-5-fluorobenzyl)-3-neopentylurea;-   3-(2-((3-chloro-1-(2,6-difluorophenyl)-1,2-dihydro-6-methyl-2-oxopyridin-4-yloxy)methyl)-5-fluorobenzyl)-1,1-dimethylurea;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-{[5-(1-hydroxy-1-methylethyl)pyridin-2-yl]methyl}-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-{[5-(hydroxymethyl)pyridin-2-yl]methyl}-6-methylpyridin-2(1H)-one;-   6-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}-N-(2-hydroxyethyl)-N-methylnicotinamide;-   6-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}-N-(2-hydroxyethyl)nicotinamide;-   6-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}-N,N-dimethylnicotinamide;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[2-(trifluoromethyl)phenyl]pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-methyl-5-vinylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-5-(1,2-dihydroxyethyl)-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-5-(hydroxymethyl)-6-methylpyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one;-   5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-2-methyl-6-oxo-1,6-dihydropyridin-3-yl]methyl    carbamate;-   5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-2-methyl-6-oxo-1,6-dihydropyridine-3-carbaldehyde;-   5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluoropbenyl)-2-methyl-6-oxo-1,6-dihydropyridine-3-carbaldehyde    oxime;-   5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-2-methyl-6-oxo-1,6-dihydropyridine-3-carbonitrile;-   4-(benzyloxy)-3-bromo-1-(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyloxy]-1-(2,6-difluorophenyl)-6-methyl-5-oxiran-2-ylpyridin-2(1H)-one;-   4-(benzylamino)-3-bromo-1-(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-methyl-5-[(E)-2-phenylethenyl]pyridin-2(1H)-one;-   ethyl    3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxo-2H-1,2′-bipyridine-5′-carboxylate;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-5′-(1-hydroxy-1-methylethyl)-6-methyl-2H-1,2-bipyridin-2-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2-furylmethyl)-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(thien-2-ylmethy)pyridin-2(1H)-one;-   3-bromo-1-(2,6-difluorophenyl)-4-(2-furylmethoxy)-6-methylpyridin-2(1H)-one;-   3-bromo-1-[2-fluoro-6-(3-furylmethoxy)phenyl]-4-(3-furylmethoxy)-6-methylpyridin-2(1H)-one;-   3-bromo-1-[2-fluoro-6-(thien-3-ylmethoxy)phenyl]-6-methyl-4-(thien-3-ylmethoxy)pyridin-2(1H)-one;-   methyl    2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-[(methylamino)carbonyl]benzoate;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-4-(1-hydroxy-1-methylethyl)-N-methylbenzamide;-   4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-chlorobenzamide;-   3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzamide;-   3-[3-chloro-4-[(2,4-difluorobenzyloxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N,4-dimethylbenzamide;-   N-{3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-4-fluorobenzyl}propanamide;-   N-{3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-4-fluorobenzyl}dimethylurea;-   N-{3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-4-fluorobenzyl}-2-hydroxyacetamide;-   N-{3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-4-fluorobenzyl}-2-hydroxy-2-methylpropanamide;-   N-{3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-4-fluorobenzyl}glycinamide hydrochloride;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-4-fluorobenzamide;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-4-fluoro-N-methylbenzamide;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-4-fluoro-N,N-dimethylbenzamide;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-{2-fluoro-5-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-6-methylpyridin-2(1H)-one;-   3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-4-fluoro-N-(2-hydroxyethyl)-N-methylbenzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-4-fluoro-N-(2-hydroxy-2-methylpropyl)benzamide;-   methyl    4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-fluorobenzoate;-   4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}benzoic acid;-   4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}benzamide;-   4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}-N,N-dimethylbenzamide;-   4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}-N-(2-hydroxy-2-methylpropyl)benzamide;-   N-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]benzyl}-2-hydroxyacetamide;-   3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzamide;-   1-(4-aminobenzyl)-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-(3-aminobenzyl)-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}phenyl)acetamide;-   N-(4-((4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)methyl)phenyl)-2-hydroxyacetamide;-   N-(4-((4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)methyl)phenyl)-(dimethylaminosulfonylcarbonyl)amine;-   N-(3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}phenyl)acetamide;-   N-(3-((4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)methyl)phenyl)-(dimethylaminosulfonylcarbonyl)amine;-   N-(3-((4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)methyl)phenyl)-2-hydroxyacetamide;-   N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}benzyl)-N′-methylurea;-   N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}benzyl)-N′-(2-hydroxy-2-methylpropyl)urea;-   N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl})benzyl)piperidine-1-carboxamide;-   N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}benzyl)morpholine-4-carboxamide;-   N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}benzyl)piperazine-1-carboxamide hydrochloride;-   N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}benzyl)-N′-(2-hydroxyethyl)urea;-   N′-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}benzyl)-N,N-dimethylurea;-   N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}benzyl)-4-hydroxypiperidine-1-carboxamide;-   4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}-N,N-dimethylbenzenesulfonamide;-   4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}-N-(2-hydroxyethyl)benzenesulfonamide;-   4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}-N-(2-hydroxy-2-methyloropyl)benzenesulfonamide;-   3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-1-(1H-pyrazol-3-ylmethyl)-1H-pyridin-2-one;-   3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-1-(2,3-dihydro-1H-indol-5-ylmethyl)-1H-pyridin-2-one;-   5-[3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-1,3-dihydro-indol-2-one;-   N-[(5-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}pyrazin-2-yl)methyl]-N-methylmethanesulfonamide;-   Methyl    (5-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazin-2-yl)methyl(methyl)carbamate;-   N-[(5-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}pyrazin-2-yl)methyl]-2-hydroxy-N,2-dimethylpropanamide;-   5-{[3-Bromo-4-[(2,4-difluorobenzyhoxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}-N-(2-hydroxy-2-methylpropyl)pyrazine-2-carboxamide;-   1-[(5-Aminopyrazin-2-yl)methyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one    trifluoroacetate;-   3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[(3-methyl-1,2,4-triazin-6-yl)methyl]pyridin-2(1H)-one    trifluoroacetate;-   3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-(1H-indazol-5-yl)-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(1H-indazol-6-yl)-6-methylpyridin-2(1H)-one;-   methyl    2-{[(3-bromo-6-methyl-1-{2-methyl-5-[(methylamino)carbonyl]phenyl}-2-oxo-1,2-dihydropyridin-4-yl)oxy]methyl}-5-fluorobenzylcarbamate;-   methyl    2-({[3-bromo-1-(5-{[(2-hydroxyethyl)amino]carbonyl}-2-methylphenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzylcarbamate;-   methyl    2-({[3-bromo-1-(5-{[(2-hydroxy-2-methylpropyl)amino]carbonyl}-2-methylphenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzylcarbamate;-   methyl    2-({[3-bromo-1-(5-{[(2-methoxyethyl)amino]carbonyl}-2-methylphenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzylcarbamate;-   methyl    2-[({1-[5-(aminocarbonyl)-2-methylphenyl]-3-bromo-6-methyl-2-oxo-1,2-dihydropyridin-4-yl}oxy)methyl]-5-fluorobenzylcarbamate;-   N-[2-({[3-chloro-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzyl]-N′-phenylurea;-   thien-3-ylmethyl    2-({[3-chloro-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzylcarbamate;-   ethyl    2-{[(3-bromo-6-methyl-1-{2-methyl-5-[(methylamino)carbonyl]phenyl}-2-oxo-1,2-dihydropyridin-4-yl)oxy]methyl}-5-fluorobenzylcarbamate;-   3-[3-bromo-4-{[2-({[(cyclopropylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6-methyl-2-oxopyridin-1    (2H)-yl]-N,4-dimethylbenzamide;-   3-[3-bromo-4-{[2-({[(cyclopropylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6-methyl-2-oxopyridin-1    (2H)-yl]-4-methylbenzoic acid;-   methyl    3-[6-[(acetyloxy)methyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-4-methylbenzoate;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-1    (2H)-yl]-4-methylbenzoic acid;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-1    (2H)-yl]-4-methylbenzoic acid;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-1    (2H)-yl]-N-(2-hydroxyethyl)-4-methylbenzamide;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-1    (2H)-yl]-N,4-dimethylbenzamide;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-1    (2H)-yl]-4-methylbenzamide;-   (5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-{2-methyl-5-[(methylamino)carbonyl]phenyl}-6-oxo-1,6-dihydropyridin-2-yl)methyl    acetate;-   (2E)-4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-N-methylbut-2-enamide;-   methyl    5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-2-furoate;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-4-(hydroxymethyl)-N-methylbenzamide;-   2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N,N′-dimethylterephthalamide;-   2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N-(4-methylterephthalamide;-   methyl    4-(aminocarbonyl)-2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]benzoate;-   2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N1,N1,N4-trimethylterephthalamide;-   2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-[(methylamino)carbonyl]benzyl    carbamate;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluoro-4-vinylphenyl)-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[4-(1,2-dihydroxyethyl)-2,6-difluorophenyl]-6-methylpyridin-2(1H)-one;-   4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzaldehyde;-   4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzyl    carbamate;-   4-(2,4-difluorobenzyloxy)-3-chloro-6-methyl-1-((5-methylpyrazin-2-yl)methyl)pyridin-2(1H)-one;-   4-(2,4-difluorobenzyloxy)-3-chloro-1-((5-(hydroxymethyl)pyrazin-2-yl)methyl)-6-methylpyridin-2(1H)-one;-   4-(2,4-difluorobenzyloxy)-3-bromo-1-((1-(2-hydroxyacetyl)indolin-5-yl)methyl)-6-methylpyridin-2(1H)-one;-   1-((1H-pyrazol-3-yl)methyl)-4-(2,4-difluorobenzyloxy)-3-bromo-6-methylpyridin-2(1H)-one;-   3-(4-(2,4-difluorobenzyloxy)-3-chloro-6-methyl-2-oxopyridin-1(2H)-yl]-N,4-dimethylbenzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-chloro-6-methyl-2-oxopyridin-1(2H)-yl)-4-methylbenzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-chloro-6-methyl-2-oxopyridin-1(2H)-yl)-4-fluoro-N-methylbenzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-chloro-6-methyl-2-oxopyridin-1(2H)-yl)-4-chloro-N-methylbenzamide;-   3-(4-(2,4-difluorobenzyloxy)-3-chloro-6-methyl-2-oxopyridin-1(2H)-yl)-4-fluorobenzamide;-   4-(4-(2,4-difluorobenzyloxy)-3-chloro-6-methyl-2-oxopyridin-1(2H)-yl)-N,3-dimethylbenzamide;-   4-(2,4-difluorobenzyloxy)-3-chloro-1-(4-(1,2-dihydroxyethyl)-2-methylphenyl)-6-methylpyridin-2(1H)-one;-   N-(4-((4-(2,4-difluorobenzyloxy)-3-chloro-6-methyl-2-oxopyridin-1    (2H)-yl)methyl)phenyl)-2-hydroxyacetamide;-   N-(4-((4-(2,4-difluorobenzyloxy)-3-chloro-6-methyl-2-oxopyridin-1    (2H)-yl)methyl)benzyl)-1-hydroxycyclopropanecarboxamide;-   N-(4-((4-(2,4-difluorobenzyloxy)-3-chloro-6-methyl-2-oxopyridin-1    (2H)-yl)methyl)benzyl)-2-hydroxyacetamide;-   N-(4-((4-(2,4-difluorobenzyloxy)-3-chloro-6-methyl-2-oxopyridin-1    (2H))-ylmethyl)phenyl)acetamide;-   ethyl    2-((3-bromo-1-(2,6-difluorophenyl-1,2-dihydro-6-methyl-2-oxopyridin-4-yloxy)methyl)-5-fluorobenzylcarbamate;-   3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-(2-hydroxyethyl)-2-oxopyridin-1    (2H)-yl)-N,4-dimethylbenzamide;-   4-(2,4-difluorobenzyloxy)-3-bromo-1-(5-(2-hydroxyethyl)-2-methylphenyl)-6-methylpyridin-2(1H)-one;-   5-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)-2-(2-hydroxyethyl)-N,4-dimethylbenzamide;-   4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-1-(4-methyl-2-(methylsulfonyl)pyrimidin-5-yl)-pyridin-2(1H)-one;-   5-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-4-methylpyrimidine-2-carbonitrile;-   4-(2,4-difluorobenzyloxy)-1-(2-(aminomethyl)-4-methylpyrimidin-5-yl)-3-bromo-6-methylpyridin-2(1H)-one;-   4-(2,4-difluorobenzyloxy)-3-bromo-1-(2-((dimethylamino)methyl)-4-methylpyrimidin-5-yl)-6-methylpyridin-2(1H)-one;-   N-((5-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)-4-methylpyrimidin-2-yl)methyl)-2-hydroxyacetamide;-   5-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-4-methylpyrimidine-2-carboxylic acid;-   5-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-4-methylpyrimidine-2-carboxamide;-   5-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1    (2H)-yl)-N,4-dimethylpyrimidine-2-carboxamide;-   N-(4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}benzyl)-2-hydroxyacetamide;-   N-(4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}benzyl)-1-hydroxycyclopropanecarboxamide;-   4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}benzyl carbamate;-   2-[4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}phenyl)amino]-1-methyl-2-oxoethyl acetate;-   2-[4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}phenyl)amino]-1,1-dimethyl-2-oxoethyl acetate;-   {1-[3-(aminocarbonyl)phenyl]-5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxo-1,6-dihydropyridin-2-yl}methyl    acetate;

or pharmaceutically acceptable salts thereof.

43. A compound of claim 1 which is

-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-{[2-(methylthio)pyrimidin-5-yl]methyl}pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-{[2-(methylsulfonyl)pyrimidin-5-yl]methyl}pyridin-2(1H)-one;-   Ethyl    2-({[3-bromo-1-(5-{[(2-hydroxyethyl)amino]carbonyl}-2-methylphenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzylcarbamate;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[5-(1H-imidazol-2-yl)-2-methylphenyl]-6-methylpyridin-2(1H)-one    trifluoroacetate;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[5-(5-hydroxy-1H-pyrazol-3-yl)-2-methylphenyl]-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[5-(5-hydroxylsoxazol-3-yl)-2-methylphenyl]-6-methylpyridin-2(1H)-one;-   5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}-2-furamide;-   5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-2-furamide;-   1-[3,5-bis(hydroxymethyl)phenyl]-3-bromo-4-[(2,4-difluorobenzyloxy]-6-methylpyridin-2(1H)-one;-   5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]isophthalamide;-   1-[3,5-bis(1-hydroxy-1-methylethyl)phenyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[4-(hydroxymethyl)phenyl]-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[4-(1-hydroxy-1-methylethyl)phenyl]-6-methylpyridin-2(1H)-one;-   1-(5-amino-2-fluorophenyl)-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one    hydrochloride;-   N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-4-fluorophenyl}-2-hydroxyacetamide;-   N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-4-fluorophenyl}-2-hydroxy-2-methylpropanamide;-   4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]-3-fluoro-N,N-dimethylbenzamide;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[(1-glycoloyl-2,3-dihydro-1H-indol-5-yl)methyl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-1H-indol-5-yl]methyl}-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-(methoxyacetyl)-2,3-dihydro-1H-indol-5-yl]methyl}-6-methylpyridin-2(1H)-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1    (2H)-yl]methyl}-N,N-dimethylindoline-1-carboxamide; and-   3-(3-bromo-4-((2,4-difluorobenzyl)oxy)-6-methyl-2-oxopyridin-1(2H)-yl)-N,4-dimethylbenzamide    (“PH-797804”), Formula X′.

In one embodiment, the p38 kinase inhibitor is3-(3-bromo-4-((2,4-difluorobenzyl)oxy)-6-methyl-2-oxopyridin-1(2H)-yl)-N,4-dimethylbenzamide (“PH-797804”), Formula X′.

Genus X Definitions

As used herein, the term “alkenyl” refers to a straight or branchedhydrocarbon of a designed number of carbon atoms containing at least onecarbon-carbon double bond. Examples of “alkenyl” include vinyl, allyl,and 2-methyl-3-heptene.

The term “alkoxy” represents an alkyl attached to the parent molecularmoiety through an oxygen bridge. Examples of alkoxy groups include, forexample, methoxy, ethoxy, propoxy and isopropoxy.

The term “thioalkoxy” represents an alkyl attached to the parentmolecular moiety through a sulfur atom. Examples of thioalkoxy groupsinclude, for example, thiomethoxy, thioethoxy, thiopropoxy andthioisopropoxy.

As used herein, the term “alkyl” includes those alkyl groups of adesigned number of carbon atoms. Alkyl groups may be straight orbranched. Examples of “alkyl” include methyl, ethyl, propyl, isopropyl,butyl, iso-, sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl,and the like. “Cx-Cy alkyl” represents an alkyl group of the specifiednumber of carbons. For example, C1-C4 alkyl includes all alkyl groupsthat include at least one and no more than four carbon atoms. It alsocontains subgroups, such as, for example, C2-C3 alkyl or C1-C3 alkyl.

The term “aryl” refers to an aromatic hydrocarbon ring system containingat least one aromatic ring. The aromatic ring may optionally be fused orotherwise attached to other aromatic hydrocarbon rings or non-aromatichydrocarbon rings. Examples of aryl groups include, for example, phenyl,naphthyl, 1,2,3,4-tetrahydronaphthalene, indanyl, and biphenyl.Preferred examples of aryl groups include phenyl and naphthyl. The mostpreferred aryl group is phenyl. The aryl groups herein are unsubstitutedor, as specified, substituted in one or more substitutable positionswith various groups. Thus, such aryl groups can be optionallysubstituted with groups such as, for example, C1-C6 alkyl, C1-C6 alkoxy,halogen, hydroxy, cyano, nitro, amino, mono- or di-(C1-C6)alkylamino,C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy,amino(C1-C6)alkyl, mono- or di(C1-C6)alkylamino(C1-C6)alkyl.

The term “arylalkyl” refers to an aryl group, as defined above, attachedto the parent molecular moiety through an alkyl group, as defined above.Preferred arylalkyl groups include, benzyl, phenethyl, phenpropyl, andphenbutyl. More preferred arylalkyl groups include benzyl and phenethyl.The most preferred arylalkyl group is benzyl. The aryl portions of thesegroups are unsubstituted or, as specified, substituted in one or moresubstitutable positions with various groups. Thus, such aryl groups canbe optionally substituted with groups such as, for example, C1-C6alkyl,C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- ordi-(C1-C6)alkylamino, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl,C1-C6 haloalkoxy, amino(C1-C6)alkyl, mono- ordi(C1-C6)alkylamino(C1-C6)alkyl.

The term “arylalkoxyl” refers to an aryl group, as defined above,attached to the parent molecular moiety through an alkoxy group, asdefined above. Preferred arylaloxy groups include, benzyloxy,phenethyloxy, phenpropyloxy, and phenbutyloxy. The most preferredarylalkoxy group is benzyloxy.

The term “cycloalkyl” refers to a C3-C8 cyclic hydrocarbon. Examples ofcycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl. More preferred cycloalkyl groups includecyclopropyl.

The term “cycloalkylalkyl,” as used herein, refers to a C3-C8 cycloalkylgroup attached to the parent molecular moiety through an alkyl group, asdefined above. Examples of cycloalkylalkyl groups includecyclopropylmethyl and cyclopentylethyl.

The terms “halogen” or “halo” indicate fluorine, chlorine, bromine, oriodine.

The term “heterocycloalkyl,” refers to a non-aromatic ring systemcontaining at least one heteroatom selected from nitrogen, oxygen, andsulfur, wherein the non-aromatic heterocycle is attached to the core.The heterocycloalkyl ring may be optionally fused to or otherwiseattached to other heterocycloalkyl rings, aromatic heterocycles,aromatic hydrocarbons and/or non-aromatic hydrocarbon rings. Preferredheterocycloalkyl groups have from 3 to 7 members. Examples ofheterocycloalkyl groups include, for example, piperazine,1,2,3,4-tetrahydroisoquinoline, morpholine, piperidine, tetrahydrofuran,pyrrolidine, and pyrazole. Preferred heterocycloalkyl groups includepiperidinyl, piperazinyl, morpholinyl, and pyrolidinyl. Theheterocycloalkyl groups herein are unsubstituted or, as specified,substituted in one or more substitutable positions with various groups.Thus, such heterocycloalkyl groups can be optionally substituted withgroups such as, for example, C1-C6 alkyl, C1-C6 alkoxy, halogen,hydroxy, cyano, nitro, amino, mono- or di-(C1-C6)alkylamino, C2-C6alkenyl, C2-C6 alkynyl, C1-C6haloalkyl, C1-C6 haloalkoxy,amino(C1-C6)alkyl, mono- or di(C1-C6)alkylamino(C1-C6)alkyl.

The term “heteroaryl” refers to an aromatic ring system containing atleast one heteroatom selected from nitrogen, oxygen, and sulfur. Theheteroaryl ring may be fused or otherwise attached to one or moreheteroaryl rings, aromatic or non-aromatic hydrocarbon rings orheterocycloalkyl rings. Examples of heteroaryl groups include, forexample, pyridine, furan, thiophene, 5,6,7,8-tetrahydroisoquinoline andpyrimidine. Preferred examples of heteroaryl groups include thienyl,benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl,benzimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl,isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl,tetrazolyl, pyrrolyl, indolyl, pyrazolyl, and benzopyrazolyl. Preferredheteroaryl groups include pyridyl. The heteroaryl groups herein areunsubstituted or, as specified, substituted in one or more substitutablepositions with various groups. Thus, such heteroaryl groups can beoptionally substituted with groups such as, for example, C1-C6 alkyl,C1-C6alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- ordi-(C1-C6)alkylamino, C2-C6alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl,C1-C6 haloalkoxy, amino(C1-C6)alkyl, mono- ordi(C1-C6)alkylamino(C1-C6)alkyl.

The term “heteroarylalkyl” refers to a heteroaryl group, as definedabove, attached to the parent molecular moiety through an alkyl group,as defined above. Preferred heteroarylalkyl groups include,pyrazolemethyl, pyrazoleethyl, pyridylmethyl, pyridylethyl,thiazolemethyl, thiazoleethyl, imidazolemethyl, imidazoleethyl,thienylmethyl, thienylethyl, furanylmethyl, furanylethyl,isoxazolemethyl, isoxazoleethyl, pyrazinemethyl and pyrazineethyl. Morepreferred heteroarylalkyl groups include pyridylmethyl and pyridylethyl.The heteroaryl portions of these groups are unsubstituted or, asspecified, substituted in one or more substitutable positions withvarious groups. Thus, such heteroaryl groups can be optionallysubstituted with groups such as, for example, C1-C6 alkyl, C1-C6 alkoxy,halogen, hydroxy, cyano, nitro, amino, mono- or di-(C1-C6)alkylamino,C2-C6 alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy,amino(C1-C6)alkyl, mono- or di(C1-C6)alkylamino(C1-C6)alkyl.

If two or more of the same substituents are on a common atom, e.g.,di(C1-C6)alkylamino, it is understood that the nature of each group isindependent of the other.

As used herein, the term “p38 mediated disorder” refers to any and alldisorders and disease states in which p38 plays a role, either bycontrol of p38 itself, or by p38 causing another factor to be released,such as but not limited to IL-1, IL-6 or IL-8. A disease state in which,for instance, IL-1 is a major component, and whose production or action,is exacerbated or secreted in response to p38, would therefore beconsidered a disorder mediated by p38.

As TNF-beta has close structural homology with TNF-alpha (also known ascachectin), and since each induces similar biologic responses and bindsto the same cellular receptor, the synthesis of both TNF-alpha andTNF-beta are inhibited by the compounds of the present invention andthus are herein referred to collectively as “TNF” unless specificallydelineated otherwise.

The compounds of the invention may exist as atropisomers, i.e., chiralrotational isomers. The invention encompasses the racemic and theresolved atropisomers. The following illustration generically shows acompound (Z) that can exist as atropisomers as well as its two possibleatropisomers (A) and (B). This illustration also shows each ofatropisomers (A) and (B) in a Fischer projection. In this illustration,R1, R2, and R4 carry the same definitions as set forth for Formula I,Rp′ is a substituent within the definition of R5, and Rp is anon-hydrogen substituent within the definition of R5.

When the compounds described herein contain olefinic double bonds orother centers of geometric asymmetry, and unless otherwise specified, itis intended that the compounds include the cis, trans, Z- andE-configurations. Likewise, all tautomeric forms are also intended to beincluded.

Genus XI Description

Compounds of Genus XI can be prepared according to the disclosures ofU.S. Pat. Nos. 7,314,881 7,323,472, and 8,058,282, which are hereinincorporated herein by reference in their entireties.

Genus XI is characterized by compounds of Formula XI:

or stereoisomers thereof, isotopically-enriched compounds thereof,prodrugs thereof, solvates thereof, and pharmaceutically acceptablesalts thereof;wherein:

is a single or double bond;

-   R₁ is an optionally substituted aryl or an optionally substituted    heteroaryl ring;-   R₂ is a moiety selected from hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl,    C₃₋₇cycloalkylC₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl,    heteroarylC₁₋₁₀ alkyl, heterocyclic, and heterocyclylC₁₋₁₀ alkyl,    wherein each moiety, excluding hydrogen, is optionally substituted,    or-   R₂ is X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃) or C(A₁)(A₂)(A₃):-   A₁ is an optionally substituted C₁₋₁₀ alkyl;-   A₂ is an optionally substituted C₁₋₁₀ alkyl;-   A₃ is hydrogen or is an optionally substituted C₁₋₁₀ alkyl; and    wherein A₁, A₂, and A₃, excluding hydrogen, are optionally    substituted 1 to 4 times by (CR₁₀R₂₀)_(n)OR₆;-   R³ is an C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,    aryl, arylC₁₋₁₀alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic, or a heterocyclylC₁₋₁₀alkyl moiety, which moieties are    optionally substituted;-   R⁶ is hydrogen, or C₁₋₁₀ alkyl;-   R₁₀ and R₂₀ are independently selected from hydrogen or C₁₋₄alkyl;-   X is R₂, OR₂, S(O)_(m)R₂, (CH₂)_(n)N(R₁₀)S(O)_(m)R₂,    (CH₂)_(n)(R₁₀)C(O)R₂, (CH₂)_(n)NR₄R₁₄, or-   X₁ is N(R₁₀), O, S(O)_(m), or CR₁₀R₂₀;-   n is 0 or an integer having a value of 1 to 10;-   m is 0 or an integer having a value of 1 or 2; and-   q is 0 or an integer having a value of 1 to 10.

In one embodiment, the p38 kinase inhibitor from Genus XI is selectedfrom the following:

-   4-Chloro-2-methyl sulfanyl-6-phenylamino-pyrimidine-5-carbaldehyde;-   4-Chloro-6-(2,6-difluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;-   4-Chloro-6-(2-chloro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;-   4-Chloro-6-(2-fluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;-   4-Chloro-6-(1-ethyl-propylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;-   4-Chloro-6-isopropylamino-2-methyl    sulfanyl-pyrimidine-5-carbaldehyde;-   4-Chloro-6-cyclopropylamino-2-methyl    sulfanyl-pyrimidine-5-carbaldehyde;-   4-Chloro-6-(cyclopropylmethyl-amino)-2-methyl    sulfanyl-pyrimidine-5-carbaldehyde;-   2-Methyl sulfanyl-4-phenyl-6-phenylamino-pyrimidine-5-carbaldehyde;-   4-(2-Chlorophenyl)-6-(1-ethyl-propylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;-   4-(2-Chlorophenyl)-6-(2-chloro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;-   4-(2-Fluorophenyl)-6-(2-chloro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;-   4-(2-Fluoro-phenyl)-6-isopropyl amino-2-methyl    sulfanyl-pyrimidine-5-carbaldehyde;-   4-Chloro-2-methylsulfanyl-6-cyclohexylaminopyrimidine-5-carboxaldehyde;-   2-Methylsulfanyl-4-(2-methyl-4-fluorophenyl)-6-cyclohexylaminopyrimidine-5-carbaldehyde;-   4-Amino-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;-   4-Cyclopropylamino-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;-   4-(Cyclopropylmethyl-amino)-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;-   4-(2,6-Difluoro-phenylamino)-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;-   4-(2-Fluorophenyl)-6-(2-fluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;-   4-sec-Butylamino-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;-   4-(4-Fluoro-2-methyl-phenyl)-6-isopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde;-   4-Cyclopropylamino-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;-   4-(Cyclopropylmethyl-amino)-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;-   4-(4-Fluoro-2-methyl-phenyl)-6-(2-fluoro-phenyl    amino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;-   4-sec-Butylamino-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;-   4-Amino-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;-   4-Amino-6-chloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde;-   4-sec-Butylamino-6-chloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde;-   4-(2,6-Difluoro-phenylamino)-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;-   4-(1-Ethylpropylamino)-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;-   2-Methylsulfanyl-4-(2-methyl-4-fluorophenyl)-6-cyclohexylaminopyrimidine-5-carbaldehyde;-   4-Chloro-2-methylsulfanyl-6-cyclohexylaminopyrimidine-5-carboxaldehyde;    and-   8-(2,6-difluorophenyl)-2-((1,3-dihydroxypropan-2-yl)amino)-4-(4-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-7(8H)-one    (“Dilmapimod”), Formula XI′.

In one embodiment, the p38 kinase inhibitor is8-(2,6-difluorophenyl)-2-((1,3-dihydroxypropan-2-yl)amino)-4-(4-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-7(8H)-one(“Dilmapimod”), Formula XI′.

Genus XI Definitions

As used herein, “optionally substituted” unless specifically definedshall mean such groups as halogen, such as fluorine, chlorine, bromineor iodine; hydroxy; hydroxy substituted C₁₋₁₀alkyl; C₁₋₁₀ alkoxy, suchas methoxy or ethoxy; halosubstituted C₁₋₁₀ alkoxy; S(O)m alkyl, such asmethyl thio, methylsulfinyl or methyl sulfonyl; —C(O); NR_(4′)R_(14′),wherein R_(4′) and R_(14′) are each independently hydrogen or C₁₋₄alkyl, such as amino or mono or -disubstituted C₁₋₄ alkyl or wherein theR_(4′)R_(14′) can cyclize together with the nitrogen to which they areattached to form a 5 to 7 membered ring which optionally contains anadditional heteroatom selected from O/N/S; C₁₋₁₀alkyl, C₃₋₇cycloalkyl,or C₃₋₇cycloalkyl C₁₋₁₀ alkyl group, such as methyl, ethyl, propyl,isopropyl, t-butyl, etc. or cyclopropyl methyl; halosubstituted C₁₋₁₀alkyl, such CF₂CF₂H, or CF₃; an optionally substituted aryl, such asphenyl, or an optionally substituted arylalkyl, such as benzyl orphenethyl, wherein these aryl containing moieties may also besubstituted one to two times by halogen; hydroxy; hydroxy substitutedalkyl; C₁₋₁₀ alkoxy; S(O)_(m)alkyl; amino, mono & di-substituted C₁₋₄alkyl amino, such as in the NR₄R₁₄ group; C₁₋₄ alkyl, or CF₃.

Suitable pharmaceutically acceptable salts are well known to thoseskilled in the art and include basic salts of inorganic and organicacids, such as hydrochloric acid, hydrobromic acid, sulphuric acid,phosphoric acid, methane sulphonic acid, ethane sulphonic acid, aceticacid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid,succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid,phenylacetic acid and mandelic acid.

In addition, pharmaceutically acceptable salts of compounds of Formula(XI) may also be formed with a pharmaceutically acceptable cation, forinstance, if a substituent group comprises a carboxy moiety. Suitablepharmaceutically acceptable cations are well known to those skilled inthe art and include alkaline, alkaline earth, ammonium and quaternaryammonium cations.

The term “halo” or “halogens” is used herein to mean the halogens,chloro, fluoro, bromo and iodo.

The term “C1-10alkyl” or “alkyl” or “alkyl1-10” is used herein to meanboth straight and branched chain radicals of 1 to 10 carbon atoms,unless the chain length is otherwise limited, including, but not limitedto, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl and the like.

The term “cycloalkyl” is used herein to mean cyclic radicals, preferablyof 3 to 8 carbons, including but not limited to cyclopropyl,cyclopentyl, cyclohexyl, and the like.

The term “cycloalkenyl” is used herein to mean cyclic radicals,preferably of 5 to 8 carbons, which have at least one bond including butnot limited to cyclopentenyl, cyclohexenyl, and the like.

The term “alkenyl” is used herein at all occurrences to mean straight orbranched chain radical of 2-10 carbon atoms, unless the chain length islimited thereto, including, but not limited to ethenyl, 1-propenyl,2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.

The term “aryl” is used herein to mean phenyl and naphthyl.

The term “heteroaryl” (on its own or in any combination, such as“heteroaryloxy”, or “heteroaryl alkyl”) is used herein to mean a 5-10membered aromatic ring system in which one or more rings contain one ormore heteroatoms selected from the group consisting of N, O or S, suchas, but not limited, to pyrrole, pyrazole, furan, pyran, thiophene,quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, pyridazine,pyrazine, uracil, oxadiazole, oxazole, isoxazole, oxathiadiazole,thiazole, isothiazole, thiadiazole, tetrazole, triazole, indazole,imidazole, or benzimidazole.

The term “heterocyclic” (on its own or in any combination, such as“heterocyclylalkyl”) is used herein to mean a saturated or partiallyunsaturated 4-10 membered ring system in which one or more rings containone or more heteroatoms selected from the group consisting of N, O, S,or S(O)m, and m is 0 or an integer having a value of 1 or 2; such as,but not limited to, the saturated or partially saturated versions of theheteroaryl moieties as defined above, such as tetrahydropyrrole,tetrahydropyran, tetrahydrofuran, tetrahydrothiophene (includingoxidized versions of the sulfur moiety), pyrrolidine, piperidine,piperazine, morpholine, thiomorpholine (including oxidized versions ofthe sulfur moiety), or imidazolidine.

The term “aralkyl” or “heteroarylalkyl” or “heterocyclicalkyl” is usedherein to mean C₁₋₄ alkyl as defined above attached to an aryl,heteroaryl or heterocyclic moiety as also defined herein unlessotherwise indicate.

The term “sulfinyl” is used herein to mean the oxide S(O) of thecorresponding sulfide, the term “thio” refers to the sulfide, and theterm “sulfonyl” refers to the fully oxidized S(O)2 moiety.

The term “aroyl” is used herein to mean C(O)Ar, wherein Ar is as phenyl,naphthyl, or aryl alkyl derivative such as defined above, such groupinclude but are not limited to benzyl and phenethyl.

The term “alkanoyl” is used herein to mean C(O)C₁₋₁₀ alkyl wherein thealkyl is as defined above.

Genus XII Description

Compounds of Genus XII can be prepared according to the disclosure ofU.S. Pat. No. 6,147,080, which is herein incorporated herein byreference in its entirety.

Genus XII is characterized by compounds of Formula XII:

or stereoisomers thereof, isotopically-enriched compounds thereof,prodrugs thereof, solvates thereof, and pharmaceutically acceptablesalts thereof,wherein:

-   each of Q₁ and Q₂ are independently selected from phenyl and 5-6    membered heteroaryl ring systems having one nitrogen heteroatom;-   Q₁ is substituted with 1 to 4 substituents, independently selected    from halo; C₁-C₃ alkyl; C₁-C₃ alkyl substituted with —NR′₂, —OR′,    —CO₂R′, or —CONR′₂; —O—(C₁-C₃)-alkyl; —O—(C₁-C₃)-alkyl substituted    with —NR′₂, —OR′, —CO₂R′, or —CONR′₂; —NR′₂; —OCF₃; —CF₃; —NO₂;    —CO₂R′; —CONR′; —SR′; —S(O₂)N(R′)₂; —SCF₃; or —CN; and-   Q₂ is optionally substituted with up to 4 substituents,    independently selected from halo; C₁-C₃ straight or branched alkyl;    C₁-C₃ straight or branched alkyl substituted with —NR′, —NR′₂, —OR′,    —CO₂R′, or —CONR′₂; —O—(C₁-C₃)-alkyl; —O—(C₁-C₃)-alkyl substituted    with —NR′, —NR′₂, —OR′, —CO₂R′, or —CONR′₂; —NR′₂; —OCF₃; —CF₃;    —NO₂; —CO₂R′; —CONR′; —SR′; —S(O₂)N(R′)₂; —SCF₃; or —CN;-   wherein R′ is selected from hydrogen, (C₁-C₃)-alkyl or    (C₂-C₃)-alkenyl or alkynyl; and-   X is selected from —S—, —O—, —S(O)₂—, —S(O)—, —C(O)—, —N(R)—, or    —C(R)₂—;-   each R is independently selected from hydrogen or (C₁-C₃)-alkyl;-   Y is C;-   A is CR′;-   n is 1; and-   R¹ is selected from hydrogen, (C₁-C₃)-alkyl, —OH, or    —O—(C₁-C₃)-alkyl.

In one embodiments, the p38 kinase inhibitor from Genus XII is selectedfrom the following:

Cmpd # Q₁ Q₂ R_(a) R_(b) 2 4-fluorophenyl phenyl hydrogen hydrogen 32,4-dichlorophenyl phenyl hydrogen hydrogen 5 2,4-dichlorophenyl4-methylphenyl hydrogen hydrogen 6 2,6-dichlorophenyl phenyl hydrogenhydrogen 7 2-chlorophenyl phenyl hydrogen hydrogen 8 2-methylphenylphenyl hydrogen hydrogen 9 3,4-dichlorophenyl phenyl hydrogen hydrogen10 4-methoxyphenyl phenyl hydrogen hydrogen 11 2-methoxyphenyl phenylhydrogen hydrogen 12 2,6-dichlorophenyl 4-fluorophenyl hydrogen hydrogen13 2,6-dichlorophenyl phenyl methyl methyl 14 2,6-dichlorophenyl4-methylphenyl hydrogen hydrogen 15 2,6-dichlorophenyl 3-methylphenylhydrogen hydrogen 16 2,6-dichlorophenyl 3,4-dichlorophenyl hydrogenhydrogen 17 2,6-difluorophenyl phenyl hydrogen hydrogen 182,6-dichlorophenyl 2-isopropylphenyl hydrogen hydrogen 192,6-dichlorophenyl 3,4-dimethylphenyl hydrogen hydrogen 202,6-dichlorophenyl 2-ethylphenyl hydrogen hydrogen 21 2,6-dichlorophenyl3-fluorophenyl hydrogen hydrogen 22 2-fluoro-6-trifluoromethylphenylphenyl hydrogen hydrogen 23 2,6-dichlorophenyl 2-methylphenyl hydrogenhydrogen 24 2,6-dichlorophenyl 3-chloro-4-fluorophenyl hydrogen hydrogen25 2,6-dichlorophenyl 3-chlorophenyl hydrogen hydrogen 262,6-dichlorophenyl 2-carbomethoxyphenyl hydrogen hydrogen 272,6-dichlorophenyl 2-carboxyphenyl hydrogen hydrogen 282,6-dichlorophenyl 2-methyl-4-chlorophenyl hydrogen hydrogen 292,6-dichlorophenyl 2-bromophenyl hydrogen hydrogen 30 2,6-dichlorophenyl2-pyridyl hydrogen hydrogen 31 2,6-dichlorophenyl 2-methylenehydroxy-hydrogen hydrogen phenyl

Com- pound # Q₁ Q₂ A n 101 2,6-dichlorophenyl 2-carbomethoxyphenylnitrogen 1 102 2,6-dichlorophenyl 2-methylphenyl nitrogen 1 1032,6-dichlorophenyl 4-fluorophenyl nitrogen 1 104 2,6-dichlorophenyl2-carboxyphenyl nitrogen 1 105 2,6-dichlorophenyl 2-carboxamidophenylnitrogen 1 106 2,6-dichlorophenyl 2-methyl-4-chlorophenyl nitrogen 1 1072,6-dichlorophenyl 2-pyridyl nitrogen 1 108 2,6-dichlorophenyl2-methylenehydroxyphenyl nitrogen 1 109 2,6-dichlorophenyl 2-bromophenylnitrogen 1 110 2,6-dichlorophenyl phenyl carbon 1,and5-(2,6-dichiorophenyl)-2-((2,4-difluorophenyl)thio)-6H-pyrimido[1,6-b]pyridazin-6-one(“Neflamapimod”), Formula XII′.

In one embodiment, the p38 kinase inhibitor is5-(2,6-dichlorophenyl)-2-((2,4-difluorophenyl)thio)-6H-pyrimido[1,6-b]pyridazin-6-one(“Neflamapimod”), Formula XII′.

Genus XIII Description

Compounds of Genus XIII can be prepared according to the disclosure ofU.S. Pat. No. 7,521,447, which is herein incorporated herein byreference in its entirety.

Genus XIII is characterized by compounds of Formula XIII:

or stereoisomers thereof, isotopically-enriched compounds thereof,prodrugs thereof, solvates thereof, and pharmaceutically acceptablesalts thereof;wherein:

-   Ar¹ is aryl or heteroaryl, each of which may be substituted or    unsubstituted;-   A is —H, —OH, an amine protecting group, —Z_(n)—NR²R³,    —Z_(n)—NR²(C═O)R², —Z_(n)—SO₂R², —Z_(n)—SOR², —Z_(n)—SR²,    —Z_(n)—OR², —Z_(n)—(C═O)R², —Z_(n)—(C═O)OR², —Z_(n)—O—(C═O)R²,    alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl,    heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy,    —Z_(n)-cycloalkyl, —Z_(n)-heterocycloalkyl, or —Z_(n)—Ar¹, wherein    said alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl,    heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy,    —Z_(n)-cycloalkyl, —Z_(n)-heterocycloalkyl, or —Z_(n)—Ar¹ may be    substituted or unsubstituted;-   Z is alkylene of from 1 to 4 carbons, or alkenylene or alkynylene    each of from 2 to 4 carbons, wherein said alkylene, alkenylene, or    alkynylene may be substituted or unsubstituted;-   R² and R³ are independently —H, —OH, an amine protecting group, an    alcohol protecting group, an acid protecting group, a sulfur    protecting group, alkyl, allyl, alkenyl, alkynyl, heteroalkyl,    heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy,    —Z_(n)-cycloalkyl, —Z_(n)— heterocycloalkyl, or —Z_(n)—Ar¹,    -   wherein said alkyl, allyl, alkenyl, alkynyl, heteroalkyl,        heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy,        —Z_(n)-cycloalkyl, —Z_(n)-heterocycloalkyl, or Z_(n)—Ar¹ may be        substituted or unsubstituted, or        -   R² together with R³ and N forms a saturated or partially            unsaturated heterocycle ring of 1 or more heteroatoms in            said ring, wherein said heterocycle may be substituted or            unsubstituted and wherein said heterocycle may be fused to            an aromatic ring;-   B is —H, —NH₂, or substituted or unsubstituted methyl;-   E is —Z_(n)—NR²R³, —Z_(n)—(C═O)R⁴, —Z_(n)—(C═O)R⁵,    —Z_(n)—NR⁵(C═O)R⁵, —Z_(n)—O(C═O)R⁵, —Z_(n)—OR⁵, —Z_(n)—SO₂R⁵,    —Z_(n)—SOR⁵, —Z_(n)—SR⁵, or —Z_(n)—NH(C═O)NHR⁵;-   R⁴ is —NH(CHR⁶)(CH₂)_(m)OR⁵, wherein m is an integer from 1 to 4, or    —NR²R³;-   R⁵ is —H, —OH, an amine protecting group, an alcohol protecting    group, an acid protecting group, a sulfur protecting group, alkyl,    allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl,    heteroalkynyl, alkoxy, heteroalkoxy, —Z_(n)-cycloalkyl,    —Z_(n)-heterocycloalkyl, or —Z_(n)—Ar¹,    -   wherein said alkyl, allyl, alkenyl, alkynyl, heteroalkyl,        heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy,        —Z_(n)-cycloalkyl, —Z_(n)-heterocycloalkyl, or —Z_(n)—-   Ar¹ may be substituted or unsubstituted;-   R⁶ is a natural amino acid side chain, —Z_(n)—NR²R³, Z_(n)—OR⁵,    Z_(n)—SO₂R⁵, Z_(n)—SOR⁵, or Z_(n)—SR⁵; and n is 0 or 1.

In one embodiment, the p38 kinase inhibitor from Genus XIII is selectedfrom the following:

-   5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid    (2-dimethylaminoethyl)amine;-   N-(2-(dimethylamino)ethyl)-N-((5-(4-fluorophenoxy)-1-isobutyl-1H-indazol-6-yl)methyl)methanesulfonamide;-   N-(2-(dimethylamino)ethyl)-N-((5-(4-fluorophenoxy)-1-isobutyl-1H-indazol-6-yl)methyl)acetamide-   [5-(4-fluorophenoxy)-1-isobutyl-1H-indazol-6-yl]morpholin-4-yl-methanone;-   [5-(4-fluorophenoxy)-1-isobutyl-1H-indazol-6-yl]-(4-methylpiperazin-1-yl)methanone;-   5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid    (1-benzylpiperidin-4-yl)amide;-   5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid    methyl-(1-methylpiperidin-4-yl)amide;-   3-{[5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carbonyl]-amino}-pyrrolidine-1-carboxylic    acid tert-butyl ester-   (S)-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid    (1-carbamoyl-3-dimethylaminopropyl)amide-   (S)-methyl    2-(5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxamido)-4-(dimethylamino)butanoate;-   (S)-5-(2,4-difluorophenoxy)-N-(4-(dimethylamino)-1-hydroxybutan-2-yl)-1-isobutyl-1H-indazole-6-carboxamide;-   (S)-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid    (1-hydroxymethyl-3-isopropylaminopropyl)amide;-   (S)-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid    (3-dimethylamino-1-dimethylcarbamoylpropyl)amide;-   (S)-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid    (3-dimethylamino-1-methylcarbamoylpropyl)amide;-   5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid;-   {3-[5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazol-6-yloxy]-propyl}dimethylamine;-   5-(2,4-difluorophenoxy)-1-isobutyl-6-(piperidin-4-ylmethoxy)-1H-indazole;-   5-(2,4-difluorophenoxy)-1-isobutyl-6-(3-piperazin-1-yl-propoxy)-1H-indazole;-   5-(2,4-difluorophenoxy)-1-isobutyl-6-(morpholin-2-ylmethoxy)-1H-indazole;-   1-[5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;-   {3-[5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazol-6-yloxy]-propyl}dimethylamine;-   5-(2,4-difluorophenoxy)-1-isobutyl-6-(piperidin-4-ylmethoxy)-1H-indazole;-   5-(2,4-difluorophenoxy)-1-isobutyl-6-(morpholin-2-ylmethoxy)-1H-indazole;    N′-[5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazol-6-yl]-N,N-dimethylpropane-1,3-diamine;-   [5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazol-6-yl]-piperidin-4-yl-amine;-   [5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazol-6-yl]-piperidin-3-ylmethylamine;-   (S)-2-{[5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carbonyl]-amino}-4-dimethylaminobutyric    acid;-   (S)-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid    (1-hydroxymethyl-3-piperidin-1-ylpropyl)amide;-   (S)-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid    [1-(2-dimethylaminoethyl)-2-hydroxy-2-methylpropyl]amide;-   (S)-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid    {1-hydroxymethyl-3-[(2-methoxyethyl)methylamino]propyl}amide;-   (S)-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid    [3-dimethylamino-1-(2-hydroxyethylcarbamoyl)propyl]amide; and-   (5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazol-6-yl)((2-(dimethylamino)ethyl)-12-azaneyl)methanone    (“ARRY-797”), Formula XIII′.

In one embodiment, the p38 kinase inhibitor is(5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazol-6-yl)((2-(dimethylamino)ethyl)-12-azaneyl)methanone(“ARRY-797”), Formula XIII′.

Genus XIII Definitions

The term “alkyl” as used herein refers to a saturated linear orbranched-chain monovalent hydrocarbon radical of one to twelve carbonatoms, wherein the alkyl radical may be optionally substitutedindependently with one or more substituents described below. Examples ofalkyl groups include, but are not limited to, methyl, ethyl, n-propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,tert-pentyl, hexyl, isohexyl, and the like.

“Alkylene” means a linear or branched saturated divalent hydrocarbonradical of one to twelve carbon atoms, e.g., methylene, ethylene,propylene, 2-methylpropylene, pentylene, and the like.

The term “alkenyl” refers to linear or branched-chain monovalenthydrocarbon radical of two to twelve carbon atoms, containing at leastone double bond, e.g., ethenyl, propenyl, and the like, wherein thealkenyl radical may be optionally substituted independently with one ormore substituents described herein, and includes radicals having “cis”and “trans” orientations, or alternatively, “E” and “Z” orientations.

The term “alkenylene” refers to a linear or branched divalenthydrocarbon radical of two to twelve carbons containing at least onedouble bond, wherein the alkenylene radical may be optionallysubstituted independently with one or more substituents describedherein. Examples include, but are not limited to, ethenylene,propenylene, and the like.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical of two to twelve carbon atoms containing at least one triplebond. Examples include, but are not limited to, ethynyl, propynyl, andthe like, wherein the alkynyl radical may be optionally substitutedindependently with one or more substituents described herein.

The term “alkynylene” to a linear or branched divalent hydrocarbonradical of two to twelve carbons containing at least one triple bond,wherein the alkynylene radical may be optionally substitutedindependently with one or more substituents described herein.

The term “allyl” refers to a radical having the Formula RC═CHCHR,wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,aryl, heteroaryl, or any substituent as defined herein, wherein theallyl may be optionally substituted independently with one or moresubstituents described herein.

The term “cycloalkyl” refers to saturated or partially unsaturatedcyclic hydrocarbon radical having from three to twelve carbon atoms,wherein the cycloalkyl may be optionally substituted independently withone or more substituents described herein. The term “cycloalkyl” furtherincludes bicyclic and tricyclic cycloalkyl structures, wherein thebicyclic and tricyclic structures may include a saturated or partiallyunsaturated cycloalkyl fused to a saturated or partially unsaturatedcycloalkyl or heterocycloalkyl ring or an aryl or heteroaryl ring.Examples of cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and thelike.

The term “heteroalkyl” refers to saturated linear or branched-chainmonovalent hydrocarbon radical of one to twelve carbon atoms, wherein atleast one of the carbon atoms is replaced with a heteroatom selectedfrom N, O, or S, and wherein the radical may be a carbon radical orheteroatom radical (i.e., the heteroatom may appear in the middle or atthe end of the radical). The heteroalkyl radical may be optionallysubstituted independently with one or more substituents describedherein. The term “heteroalkyl” encompasses alkoxy and heteroalkoxyradicals.

The term “heterocycloalkyl” refers to a saturated or partiallyunsaturated cyclic radical of 3 to 8 ring atoms in which at least onering atom is a heteroatom selected from nitrogen, oxygen and sulfur, theremaining ring atoms being C where one or more ring atoms may beoptionally substituted independently with one or more substituentdescribed below and wherein the heterocycloalkyl ring can be saturatedor partially unsaturated. The radical may be a carbon radical orheteroatom radical. “Heterocycloalkyl” also includes radicals whereheterocycle radicals are fused with aromatic or heteroaromatic rings.Examples of heterocycloalkyl rings include, but are not limited to,pyrrolidine, piperidine, piperazine, tetrahydropyranyl, morpholine,thiomorpholine, homopiperazine, phthalimide, and derivatives thereof.

The term “heteroalkenyl” refers to linear or branched-chain monovalenthydrocarbon radical of two to twelve carbon atoms, containing at leastone double bond, e.g., ethenyl, propenyl, and the like, wherein at leastone of the carbon atoms is replaced with a heteroatom selected from N,O, or S, and wherein the radical may be a carbon radical or heteroatomradical (i.e., the heteroatom may appear in the middle or at the end ofthe radical). The heteroalkenyl radical may be optionally substitutedindependently with one or more substituents described herein, andincludes radicals having “cis” and “trans” orientations, oralternatively, “E” and “Z” orientations.

The term “heteroalkynyl” refers to a linear or branched monovalenthydrocarbon radical of two to twelve carbon atoms containing at leastone triple bond. Examples include, but are not limited to, ethynyl,propynyl, and the like, wherein at least one of the carbon atoms isreplaced with a heteroatom selected from N, O, or S, and wherein theradical may be a carbon radical or heteroatom radical (i.e., theheteroatom may appear in the middle or at the end of the radical). Theheteroalkynyl radical may be optionally substituted independently withone or more substituents described herein.

The term “heteroallyl” refers to radicals having the Formula RC═CHCHR,wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,aryl, heteroaryl, or any substituent as defined herein, wherein at leastone of the carbon atoms is replaced with a heteroatom selected from N,O, or S, and wherein the radical may be a carbon radical or heteroatomradical (i.e., the heteroatom may appear in the middle or at the end ofthe radical). The heteroallyl may be optionally substitutedindependently with one or more substituents described herein.

“Aryl” means a monovalent aromatic hydrocarbon monocyclic radical of 6to 10 ring atoms or a polycyclic aromatic hydrocarbon, optionallysubstituted independently with one or more substituents describedherein. More specifically the term aryl includes, but is not limited to,phenyl, 1-naphthyl, 2-naphthyl, and derivatives thereof.

“Heteroaryl” means a monovalent monocyclic aromatic radical of 5 to 10ring atoms or a polycyclic aromatic radical, containing one or more ringheteroatoms selected from N, O, or S, the remaining ring atoms being C.The aromatic radical is optionally substituted independently with one ormore substituents described herein. Examples include, but are notlimited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl,imidazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl,thiazolyl, and derivatives thereof.

The term “halo” represents fluoro, chloro, bromo or iodo.

“Amino protecting groups” refers to those organic groups intended toprotect nitrogen atoms against undesirable reactions during syntheticprocedures and include, but are not limited to, benzyl,benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trifluoroacetyl, andthe like.

“Alcohol protecting groups” refers to those organic groups intended toprotect alcohol groups or substituents against undesirable reactionsduring synthetic procedures and include, but are not limited to,(trimethylsilyl)ethoxymethyl (SEM), tert-butyl, methoxymethyl (MOM), andthe like.

“Sulfur protecting groups” refers to those organic groups intended toprotect sulfur groups or substituents against undesirable reactionsduring synthetic procedures and include, but are not limited to, benzyl,(trimethylsilyl)ethoxymethyl (SEM), tert-butyl, trityl and the like.

“Acid protecting groups” refers to those organic groups intended toprotect acid groups or substituents against undesirable reactions duringsynthetic procedures and include, but are not limited to, benzyl,(trimethylsilyl)ethoxymethyl (SEM), methylethyl and tert-butyl esters,and the like.

In one embodiment, the p38 kinase inhibitor may be selected from thefollowing:2-(4-Chlorophenyl)-4-(fluorophenyl)-5-pyridin-4-yl-1,2-dihydropyrazol-3-one,RWJ-67657, RDP-58, Scios-469 (talmapimod), SB-210313, SB-220025,SB-238039, HEP-689, SB-203580, SB-239063, SB-239065, SB-242235, VX-702and VX-745, AMG-548, BIRB-796 (Doramapimod), RO 4402257 (Pamapimod),FR-167653, SB-681323 (Dilmapimod), SB-281832, SC-040, SC-XX906,CP-64131, CNI-1493, RPR-200765A, Ro-320-1195, AIK-3, AKP-OO1, LLZ1640-2, ARRY-614, ARRY-797, AS-1940477, AVE-9940, AZD-7624, BCT-197,BIRB-1017BS, BMS-582949, CAY10571, CBS-3595, CCT-196969, CCT-241161,CDP-146, CGH 2466, CHR-3620, Chlormethiazole edisylate, and CM PD-1.

In one embodiment, the p38 kinase inhibitor is selected from thefollowing: Doramapimod, EO 1428, FY-101C, FX-005, GSK-610677 HE-3286,HSB-13, JX 401, KC-706, KC-706 (ITX-5061), LEO-15520, LEO-1606,Losmapimod, LP-590, LY-30007113, LY2228820, M L 3403, OX-27-NO, NP-202,pexmetinib, PF-03715455, PH-797804, PS-540446, ralimetinib, regorafenib,RO-3201195, RWJ 67657, RWJ-67657, SB 202190, SB 203580, SB 203580hydrochloride, SB202190, SB202190 hydrochloride, SB-681323, SB-856553,SC-80036, SCD-282, SCIO-323, SCIO-469, SD-06, semapimod, SKF 86002, SXOil, SYD-003, TA-5493, TAK 715, TOP-1210, TOP-1630, UR-13870, UR-13870,VGX-1027.27,8-(2,6-difluorophenyl)-2-(1,3-dihydroxypropan-2-ylamino)-4-(4-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-7-one(Dilmapimod), and GSK-610677.

In one embodiment, the p38 kinase inhibitor is selected from thefollowing:6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-N-(2,2-dimethylpropyl)pyridine-3-carboxamide(Losmapimod),5-[(2-chloro-6-fluorophenyl)acetylamino]-3-(4-fluorophenyl)-4-(4-pyrimidinyl)isoxazole(AKP-001), KC-706,(1-[5-tert-butyl-2-(3-chloro-4-hydroxyphenyl)pyrazol-3-yl]-3-[[2-[[3-[2-(2-hydroxyethylsulfanyl)phenyl]-[1,2,4]triazolo[4,3-a]pyridin-6-yl]sulfanyl]phenyl]methyl]urea)(PF-03715455),(3-[3-bromo-4-[(2,4-difluorophenyl)methoxy]-6-methyl-2-oxopyridin-1-yl]-N,4-dimethylbenzamide)(PH-797804), RV-7031.29,2-methoxy-1-{4-[(4-{3-[5-(tert-butyl)-2-(p-tolyl)-2H-pyrazol-3-yljureido}-1,AMG-548, BIRB-796 (Doramapimod), RO 4402257 (Pamapimod), FR-167653SB-681323 (Dilmapimod), SB-281832, SC-040, and SC-XX906, CP-64131,CNI-1493, RPR-200765A, Ro-320-1195, AIK-3, AKP-OO1, LL Z1640-2,ARRY-614, ARRY-797, AS-1940477, AVE-9940, AZD-7624, BCT-197,BIRB-1017BS, BMS-582949, CAY10571, CBS-3595, CCT-196969, CCT-241161,CDP-146, CGH 2466, CHR-3620, Chlormethiazole edisylate, and CM PD-1.

In one embodiment, the p38 kinase inhibitor is selected from thefollowing: Doramapimod, EO 1428, FY-101C, FX-005, GSK-610677 HE-3286,HSB-13, JX 401, KC-706, KC-706 (ITX-5061), LEO-15520, LEO-1606,Losmapimod, LP-590, LY-30007113, LY2228820, M L 3403, OX-27-NO, NP-202,pexmetinib, PF-03715455, PH-797804, PS-540446, ralimetinib, regorafenib,RO-3201195, RWJ 67657, RWJ-67657, SB 202190, SB 203580, SB 203580hydrochloride, SB202190, SB202190 hydrochloride, SB-681323, SB-856553,SC-80036, SCD-282, SCIO-323, SCIO-469, SD-06, semapimod, SKF 86002, SXOil, SYD-003, TA-5493, TAK 715, TOP-1210, TOP-1630, UR-13870, UR-13870,and VGX-1027, SB 203580, SB 203580 hydrochloride, SB681323 (Dilmapimod),and LY2228820 dimesylate.

In one embodiment, the p38 kinase inhibitor is selected from thefollowing: BIRB 796 (Doramapimod), BMS-582949, Pamapimod, GW856553,ARRY-797AL 8697, AMG 548, CMPD-1, EO 1428, JX 401, RWJ 67657, TA 01, TA02, VX 745, DBM 1285 dihydrochloride, ML 3403, SB 202190, SB 239063, SB706504, SCIO 469 hydrochloride, SKF 86002 dihydrochloride, SX Oil, TAK715, VX 702, and PH797804.

In one embodiment, the p38 kinase inhibitor is characterized by acompound of Genus XXX.

In one embodiment, the p38 kinase inhibitor is characterized by acompound of Formula (XXX′):

or stereoisomers thereof, isotopically-enriched compounds thereof,prodrugs thereof, solvates thereof, and pharmaceutically acceptablesalts thereof.

Genus XXX Description

Compounds of Genus XXX can be prepared according to the disclosure ofU.S. Pat. No. 8,633,312 which is herein incorporated herein by referencein its entirety.

Genus XXX is characterized by compounds of Formula (XXX′):

or stereoisomers thereof, isotopically-enriched compounds thereof,prodrugs thereof, solvates thereof, and pharmaceutically acceptablesalts thereof;wherein:

-   one of the ring atoms X and Y represents CH₂ and the other    represents O, S, SO, SO₂ or NR₅, or —X—Y— is —CH₂—CH₂— or —CH═CH—;-   R¹ is selected from:-   A) RO—, wherein R is chosen from:    -   a) C₁-C₆-alkyl, which is substituted by 1, 2 or 3 hydroxyl or        C-CG-alkoxy groups;    -   b) C₁-C₆-alkyl, which is substituted by a saturated or        unsaturated, non-aromatic heterocyclic radical having 5 or 6        ring atoms, which contains 1, 2 or 3 hetero atoms which are        chosen independently of each other from O, N and S, wherein the        heterocyclic radical can optionally contain 1 or 2 hydroxy,        C₁-C₆-alkoxy or C₁-C₆-alkyl substituents and can be condensed        with a phenyl ring or a saturated or unsaturated carbocyclic        radical having 5 or 6 ring atoms;    -   c) a non-aromatic heterocyclic radical having 5 or 6 ring atoms,        which contains 1 or 2 hetero atoms which are chosen        independently of each other from O and N;    -   d) C₁-C₆-alkyl;    -   e) H;    -   f) C₁-C₆-alkyl, which is substituted by NR₆R7;    -   g) CF₃SO₂—;    -   h) C₁-C₆-alkylcarbonyloxy-C₁-C₆-alkyl; and    -   i) (C₃-C₇-cycloalkyl)-C₁-C₆-alkyl, which can optionally contain        1 or 2 hydroxy, C₁-C₆-alkoxy or C₁-C₆-alkyl substituents on the        cycloalkyl radical;-   B) NR₆R₇;-   C) tetrazolo; and-   D) NR₈CONR₁₃R₁₄;-   R₂ is H or C₁-C₆-alkyl;-   R₃ is selected from:

-   R₄ is H, halogen or C₁-C₆-alkyl;-   R₅ is H or C₁-C₆-alkyl,    -   wherein the C₁-C₆ alkyl is substituted by 1, 2 or 3 hydroxyl or        C₁-C₆-alkoxy groups;-   R₆ and R₇ are each independently H or C₁-C₆-alkyl, which is    substituted by 1, 2 or 3 hydroxyl or C₁-C₆-alkoxy groups;    -   R₅ is H or C₁-C₆-alkyl;-   R₉, R₁₀, and R₁₁, are each independently selected from H, NH₂,    mono-C₁-C₆-alkylamino, di-C₁-C₆-alkylamino, C₁-C₆-alkyl,    C₁-C₆-alkoxy, hydroxyl, halogen, C₁-C₆-alkyl, which is substituted    by 1, 2 or 3 halogen atoms; CONR₆R₇; and NO₂;-   R₁₂ represents H or NH₂;-   R₁₃ and R₁₄, are independently selected from H or C₁-C₆-alkyl, or    -   R¹³ and R¹⁴ are taken together with the nitrogen atom to which        they are bonded to form a non-aromatic heterocyclic radical        having 5 or 6 ring atoms, which contains 1 or 2 hetero atoms        which are chosen independently of each other from O and N.

In one embodiment, the p38 kinase inhibitor from Genus XXX is selectedfrom the following:

-   (1) 2-(2-aminoanilino)-7-methoxydibenzosuberone;-   (2) 2-(2-amino-4-fluoroanilino)-7-methoxydibenzosuberone;-   (3) 2-(2,4-difluoroanilino)-7-methoxydibenzosuberone;-   (4) 2-(2-chloro-4-fluoroanilino)-7-methoxydibenzosuberone;-   (5) 2-(2,4,5-trifluoroanilino)-7-methoxydibenzosuberone;-   (6) 2-(2-trifluoromethylanilino)-7-methoxydibenzosuberone;-   (7) 2-(anilino)-7-methoxydibenzosuberone;-   (8) 2-(2-methoxyanilino)-7-methoxydibenzosuberone;-   (9) 2-(3-methyl-4-fluoroanilino)-7-methoxydibenzosuberone;-   (10) 2-(2-amino-4-trifluoromethylanilino)-7-methoxydibenzosuberone;-   (11) 2-(phenyl)-7-methoxydibenzosuberone;-   (12) 2-(2,4-difluoroanilino)-7-methoxydibenzosuberenone;-   (13)    2-(2,4-difluoroanilino)-7-(S-1,2-isopropylideneglycer-3-yl)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one;-   (14)    2-(2,4-difluoroanilino)-7-(R-1,2-isopropylideneglycer-3-yl)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one;-   (15)    2-(2-aminoanilino)-7-(S-1,2-isopropylideneglycer-3-yl)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one;-   (16)    2-(2-aminoanilino)-7-(R-1,2-isopropylideneglycer-3-yl)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one;-   (17)    2-(2,4-difluoroanilino)-7-[2R-,3-dihydroxypropoxy]-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one;-   (18)    2-(2,4-difluoroanilino)-7-[2S-,3-dihydroxypropoxy]-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one;-   (19)    2-(2-aminoanilino-7-[2R-,3-dihydroxypropoxy]-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one;-   (20)    2-(2-aminoanilino-7-[2S-,3-dihydroxypropoxy]-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one;-   (21)    2-(2,4-difluoroanilino)-7-(2-hydroxy-ethoxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one;-   (22)    2-(2,4-difluoroanilino)-7-(3-hydroxy-propoxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one;-   (23)    2-(2,4-difluoroanilino)-7-(2-morpholin-4-yl-ethoxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one;-   (24)    2-(2-aminoanilino)-7-(2-morpholin-4-yl-ethoxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one;-   (25)    2-(2,4-difluoroanilino)-7-(2-tetrahydropyran-4-yl-oxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one;-   (26)    (S)-2-(2,4-difluorophenylamino)-8-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one;-   (27)    (R)-2-(2,4-difluorophenylamino)-8-(2,3-dihydroxypropoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one;-   (28)    (S)-2-(2-aminophenylamino)-8-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one;-   (29)    (R)-2-(2-aminophenylamino)-8-(2,3-dihydroxypropoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one;-   (30)    2-(2,4-difluorophenylamino)-8-(2-morpholin-4-yl-ethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one;-   (31)    8-(2,4-difluorophenylamino)-1-hydroxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one;-   (32)    8-(2,4-difluorophenylamino)-1-methoxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one;-   (33)    8-(2-aminophenylamino)-1-methoxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one;-   (34)    (S)-8-(2,4-difluorophenylamino)-1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one;-   (35)    (R)-8-(2,4-difluorophenylamino)-1-(2,3-dihydroxypropoxy)-10,11-dihydrodibenzo-[a,d]cyclohepten-5-one;-   (36)    (S)-8-(2-aminophenylamino)-1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one;-   (37)    (R)-8-(2-aminophenylamino)-1-(2,3-dihydroxypropoxy)-10,11-dihydrodibenzo-[a,d]cyclo-hepten-5-one;-   (38)    8-(2,4-difluorophenylamino)-1-(tetrahydropyran-4-yloxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one;-   (39)    8-(2,4-difluorophenylamino)-1-(2-morpholin-4-yl-ethoxy)-10,11-dihydrodibenzo-[a,d]cyclo-hepten-5-one;-   (40)    3-(2,4-difluorophenylamino)-8-amino-6H-dibenzo[b,e]oxepin-11-one;-   (41) 3-(2-aminophenylamino)-8-amino-6H-dibenzo[b,e]oxepin-11-one;-   (42) 8-amino-3-(2-methoxyphenylamino)-6H-dibenzo[b,e]oxepin-11-one;-   (43)    8-amino-3-(4-fluoro-2-methoxyphenylamino)-6H-dibenzo[b,e]-oxepin-11-one;-   (44)    8-amino-3-(2-amino-4-trifluoromethylphenylamino)-6H-dibenzo[b,e]oxepin-11-one;-   (45) 8-amino-3-(tetrazol-1-yl)-6H-dibenzo[b,e]oxepin-11-one;-   (46)    3-(2,4-difluorophenylamino)-8-tetrazol-1-yl-6H-dibenzo[b,e]oxepin-11-one;-   (47) 2-(2-methyl-4-Fluoroanilino)-7-methoxydibenzosuberone;-   (48) 2-(2-chloroanilino)-7-methoxydibenzosuberone;-   (49)    2-(2-amino-4-fluoroanilino)-7-hydroxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one;-   (50)    2-(2,4-difluoroanilino)-7-hydroxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one;-   (51)    2-(2-chloro-4-fluoroanilino)-7-hydroxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one;-   (52)    2-(2-chloroanilino)-7-hydroxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one;-   (53)    2-(anilino)-7-hydroxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one;-   (54)    2-(2,4-difluoroanilino)-7-hydroxy-dibenzo[a,d]-cyclohepten-5-one;-   (55)    2-(2,4-difluoroanilino)-7-[3-(4-Hydroxypiperidin-4-yl-propoxy)]-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one;-   (56)    3-(2-amino-4-fluorophenylamino)-8-nitro-6H-dibenzo[b,e]oxepin-11-one;-   (57) morpholine-4-carboxylic acid    [3-(2,4-difluorophenylamino)-1-oxo-6,11-dihydrodibenzo[b,e]oxepin-8-yl]amide;    and-   (R)-2-((2,4-difluorophenyl)amino)-7-(2,3-dihydroxypropoxy)-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one    (“skepinone-L”), Formula XXX′.

In one embodiment, the p38 inhibitor is(R)-2-((2,4-difluorophenyl)amino)-7-(2,3-dihydroxypropoxy)-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one(“skepinone-L”), Formula XXX′.

Genus V Definitions

The expression “alkyl” (also in combination with other groups, such asalkoxy, haloalkyl etc.) includes straight-chain and branched alkylgroups having preferably 1 to 6 or 1 to 4 carbon atoms, such as methyl,ethyl, n- and i-propyl, n-, i- and t-butyl, sec-butyl, n-pentyl andn-hexyl.

The expression “halogen” stands for a fluorine, chlorine, bromine oriodine atom, in particular for a fluorine or chlorine atom.

C₁-C₆-Alkoxy which is substituted by 1, 2 or 3 hydroxyl or C₁-C₆-alkoxygroups is preferably C₂-C₆-alkoxy, in particular 2-hydroxyethoxy,3-hydroxypropoxy, 2-hydroxypropoxy, 1,2-dihydroxyethoxy,2,3-dihydroxypropoxy or 2,3-dimethoxypropoxy.

A saturated non-aromatic heterocyclic radical is, in particular,pyrrolidinyl, piperidinyl, hydroxypiperidinyl, piperazinyl,tetrahydropyranyl, tetrahydrofuranyl, dioxolanyl,2,2-dimethyldioxolanyl, dioxanyl, morpholinyl or thiomorpholinyl. Thepiperidinyl radical can be substituted by 1, 2, 3 or 4 C₁-C₄-alkylgroups, in particular methyl groups. A preferred piperidinyl radical is2,2,6,6-tetramethylpiperidinyl. The nitrogen-containing heterocyclicradicals can be bonded via a nitrogen atom or a carbon atom.

An unsaturated non-aromatic heterocyclic radical is, in particular,pyrrolinyl, di- or tetrahydropyridinyl.

An aromatic heterocyclic radical is, in particular, pyridyl, preferably3- or 4-pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, furyl, thienyl, thiazolyl, thiadiazolyl, isothiazolyl or thecorresponding benzo derivatives thereof.

In several embodiments, a method for treating a disorder responsive top38 kinase inhibition is provided. The method may include administeringto a subject in need thereof, an effective amount of a p38 agent, or astereoisomer thereof, an isotopically-enriched compound thereof, aprodrug thereof, a solvate thereof, or a pharmaceutically acceptablesalt thereof. The method includes the treatment of disorders associatedwith DUX4 gene expression, wherein the inhibition of p38 kinase with ap38 agent may reduce DUX4 expression levels and/or the expression of oneor more downstream genes in cells of the subject.

In some embodiments, the p38 agent may be selected from any of the p38kinase inhibitors described herein, and/or selected from the compoundsdescribed in any of the following patents and publications, orcorresponding U.S. patents and publications that were available at thetime that the priority application was filed, i.e., Oct. 5, 2017:

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The above-listed patents and publications are incorporated herein byreference herein in their entireties.

The present disclosure provides methods of reducing the expression aDUX4-fl mRNA, a DUX4 polypeptide, or a polypeptide encoded by adownstream target gene of DUX4, in cells, comprising contacting thecells with a p38 agent that results in a reduction of active p38 proteinin the cell, thereby reducing expression the DUX4 polypeptide or thepolypeptide encoded by the downstream target gene of DUX4. These methodsmay be practiced using a variety of different types of p38 agents, andfor modulating a variety of different biological processes in the cell,such as inhibiting apoptosis, as well as for treating subjects fordiseases associated with aberrant DUX4 expression, such as FSHD. Inparticular embodiments, the p38 protein is p38-α and/or p38-β. Inparticular embodiments, the p38 protein is not p38-γ. In certainembodiments, the p38 agent binds a p38 protein, e.g., p38-α or p38-β, orbinds a polynucleotide encoding the p38 protein, e.g., p38-α or p38-β,or an antisense polynucleotide thereof.

In certain embodiments of any of the methods disclosed herein, the cellis a muscle cell, optionally a terminally differentiated muscle cell. Insome embodiments, the cell has an increased expression level of theDUX4-fl mRNA, the DUX4 polypeptide, or the polypeptide encoded by thedownstream target gene, as compared to the expression level of theDUX4-fl mRNA, the DUX4 polypeptide, or the polypeptide encoded by thedownstream target gene, in a control cell, e.g., a cell obtained from ahealthy subject. In some embodiments, the increased expression level ofthe DUX4-fl mRNA, the DUX4 polypeptide, or the polypeptide encoded bythe downstream target gene, is due to reduced repression at a D4Z4 locusin the cell. In certain embodiments, the cell is associated withfacioscapulohumeral muscular dystrophy (FSHD), e.g., it was obtainedfrom a subject diagnosed with FSHD or is present within a subjectdiagnosed with FSHD. In some embodiments, the cell comprises a deletionof one or more macrosatellite D4Z4 repeats in the subtelomeric region ofchromosome 4q35, optionally wherein the cell comprises <7 macrosatelliteD4Z4 repeats in the subtelomeric region of chromosome 4q35. In someembodiments, the cell comprises one or more mutations in a StructuralMaintenance Of Chromosomes Flexible Hinge Domain Containing 1 (SMCHD1)gene. In some embodiments, the cell comprises at least one non-deleted4qA allele. In certain embodiments of the methods disclosed herein, thep38 agent inhibits the expression or activity, or reduces the amount, ofthe p38 protein, wherein the activity is optionally kinase activity.

In some embodiments, the p38 agent inhibits the expression of the p38protein. In particular embodiments, the p38 agent binds a polynucleotideencoding the p38 protein, or binds an antisense polynucleotide thereof.In particular embodiments, the p38 agent comprises or consists of anucleic acid, optionally a DNA, RNA, guide RNA (gRNA), short hairpin RNA(shRNA), small interfering RNA (siRNA), or antisense oligonucleotide.

In some embodiments, the p38 agent inhibits the activity of the p38protein. In particular embodiments, the p38 agent binds the p38 protein.In particular embodiments, the p38 agent comprises or consists of apolypeptide, optionally a protein, a peptide, a protein mimetic, apeptidomimetic, or an antibody or functional fragment thereof. In someembodiments, the p38 agent comprises a small molecule, optionally asmall organic molecule or a small inorganic molecule.

In certain embodiments of any of the methods disclosed herein, thedownstream target gene is RFPL2, CCNA1, SLC34A2, TPRX1, KHDC1L, ZSCAN4,PRAMEF20, TRIM49, PRAMEF4, PRAME6, PRAMEF15 or ZNF280A.

In particular embodiments of any of the methods disclosed herein, theexpression or the activity of the p38 protein, or the amount of the p38protein, is reduced by at least 10%, at least 20%, at least 30%, atleast 40%, at least 50%, at least 60%, at least 70%, at least 80%, atleast 90%, at least 95%, at least 98%, at least 99%, or 100%.

In a related embodiment, the present disclosure provides a method oftreating or preventing a disease or disorder associated with increasedexpression of a DUX4-fl mRNA, a DUX4 protein, or a polypeptide encodedby a downstream target gene of DUX4, in a subject in need thereof,comprising providing to the subject a pharmaceutical compositioncomprising an p38 agent that results in a reduction in the amount ofactive p38 protein in one or more tissue of the subject, therebyreducing expression of the DUX4-fl mRNA, the DUX4 protein, or thepolypeptide encoding the downstream target gene in one or more tissue ofthe subject.

In many embodiments, the cells are muscle cells. In some embodiments,the cells are terminally-differentiated muscle cells.

In some embodiments, the cells include one or more mutations in aStructural Maintenance Of Chromosomes Flexible Hinge Domain Containing 1(SMCHD1) gene. In some embodiments, the cells may include at least onenon-deleted 4qA allele.

In many embodiments, the cells may include an increased expression levelof a DUX4 polypeptide, or a polypeptide encoded by one or moredownstream target genes, as compared to the expression level of a DUX4polypeptide, or a polypeptide encoded by one or more downstream targetgenes in a control cell.

In many embodiments, the DUX4 is a DUX4 full length (DUX4-fl).

In some embodiments, the cells may be associated with FSHD.

In some embodiments, the disorder is associated with DUX4 geneexpression.

In some embodiments, the disorder is associated with DUX4 geneexpression and the DUX4 gene expression may result from the subjecthaving less than 10 D4Z4 repeats in the subtelomeric region ofchromosome 4q35. In some embodiments, the cells may include a deletionof one or more macrosatellite D4Z4 repeats in the subtelomeric region ofchromosome 4q35. In other embodiments, the cells may include less than 7macrosatellite D4Z4 repeats in the subtelomeric region of chromosome4q35.

In some embodiments, the cells may include a dysregulated D4Z4 array atchromosome 4q35 prior to administration of the p38 agent. In oneembodiment, the cells may include a dysregulated D4Z4 array includingfewer than 11 repeat units. In some embodiments, the dysregulated D4Z4array may include fewer than 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 repeatunits.

In some embodiments, the cells are muscle cells and the cells mayinclude a dysregulated D4Z4 array at chromosome 4q35 prior toadministration of the p38 agent. In one embodiment, the muscles cellsmay include a dysregulated D4Z4 array including fewer than 11 repeatunits. In some embodiments, the dysregulated D4Z4 array may includefewer than 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 repeat units.

In some embodiments, the disorder is FSHD. FSHD may include one or moreof FSHD1 and FSHD2. In one embodiment, the disorder is FSHD1. In anotherembodiment, the disorder is FSHD2. In one embodiment, the disorder isFSHD1 and FSHD2.

In one embodiment, the disorder is ICF.

In one embodiment, the disorder is ALS.

In one embodiment, the disorder is IBM.

In one embodiment, the disorder is cancer. The cancer may be selectedfrom Ewing's sarcoma, soft tissue sarcoma, rhabdomyosarcoma, and adultand pediatric B-cell acute lymphoblastic leukemia.

In some embodiments, the disorder may be selected from one or more of:FSHD1, FSHD2, ICF, ALS, IBM, Ewing's sarcoma, soft tissue sarcoma,rhabdomyosarcoma, and adult and pediatric B-cell acute lymphoblasticleukemia.

In one embodiment, the subject is identified as having FSHD based uponthe presence of a transcriptionally active DUX4. In another embodiment,the subject is identified as having FSHD based upon the presence of oneor more downstream genes ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2, KHDC1L,RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6,PRAMEF15, and ZNF280A in muscle. In another embodiment, the subject isidentified as having FSHD based upon the presence of increasedexpression levels of one or more downstream genes ZSCAN4, LEUTX,PRAMEF2, TRIM43, MBD3L2, KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20,TRIM49, PRAMEF4, PRAME6, PRAMEF15, and ZNF280A relative to a healthycontrol. In another embodiment, the subject is identified as having FSHDbased upon the presence of a transcriptionally active DUX4 and thepresence of downstream genes ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2,KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6,PRAMEF15, and ZNF280A.

In another embodiment, the method may include measuring the expressionlevel of one or more of: DUX4, ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2,KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6,PRAMEF15, and ZNF280A in the subject prior to the administration of thep38 agent. The method may further include determining that the subjectis in need of treatment if the expression level of one or more of: DUX4,ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2, KHDC1L, RFPL2, CCNA1, SLC34A2,TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6, PRAMEF15, and ZNF280A is/areelevated relative to a healthy control.

In another embodiment, the method may include measuring the expressionlevel of one or more of: DUX4, ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2,KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6,PRAMEF15, and ZNF280A in the cells of the subject before and after theadministration of the p38 agent. The method may include comparing theexpression level of one or more of: DUX4, ZSCAN4, LEUTX, PRAMEF2,TRIM43, MBD3L2, KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49,PRAMEF4, PRAME6, PRAMEF15, and ZNF280A in the subject before and afterthe administration of the p38 agent. The method may include determiningthe effectiveness of treatment by the comparing of the expression levelof one or more of: DUX4, ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2, KHDC1L,RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6,PRAMEF15, and ZNF280A before and after the administration of the p38agent, wherein a decrease in the expression level(s) is indicative ofeffective treatment.

In some embodiments, the p38 agent reduces one or more downstream genesselected from ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2, KHDC1L, RFPL2,CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6, PRAMEF15, andZNF280A.

In one embodiment, the p38 agent reduces MBD3L2.

In one embodiment, the p38 agent reduces ZSCAN4.

In one embodiment, the p38 agent reduces LEUTX.

In one embodiment, the p38 agent reduces PRAMEF2.

In one embodiment, the p38 agent reduces TRIM43.

In one embodiment, the p38 agent reduces KHDC1L.

In one embodiment, a transcriptional modulator of DUX4 and downstreamgenes ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2, KHDC1L, RFPL2, CCNA1,SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6, PRAMEF15, and ZNF280Aare inhibited by p38 kinase.

In some embodiments, the administering may be combined with clinicalmanagement involving physical therapy, aerobic exercise, respiratoryfunction therapy, orthopedic interventions.

In some embodiments, the administering includes administering of the p38agent with another pharmaceutical agent.

In some embodiments, the administering includes administering of the p38agent with another pharmaceutical agent for the treatment of FSHD.

In some embodiments, the administering causes a decrease in muscledegeneration.

In some embodiments, the administering causes a reduction in apoptosisof muscle cells in the subject. In one embodiment, the muscles cells areterminally differentiated.

In several embodiments, a method for treating facioscapulohumeralmuscular dystrophy (FSHD) is provided. The method may includeadministering to a subject in need thereof, an effective amount of a p38agent described herein, or a stereoisomer thereof, anisotopically-enriched compound thereof, a prodrug thereof, a solvatethereof, or a pharmaceutically acceptable salt thereof.

In some embodiments, the disorder is FSHD. FSHD may include one or moreof FSHD1 and FSHD2. In one embodiment, the disorder is FSHD1. In anotherembodiment, the disorder is FSHD2. In one embodiment, the disorder isFSHD1 and FSHD2.

Modified Compounds of the Invention

A modified compound of any one of such compounds including amodification having an improved, e.g., enhanced, greater, pharmaceuticalsolubility, stability, bioavailability and/or therapeutic index as acompared to the unmodified compound is also contemplated. The examplesof modifications include by not limited to the prodrug derivatives, andisotopically-labeled compounds, e.g., deuterium-enriched compounds.

Prodrug derivatives: prodrugs, upon administration to a subject, willconverted in vivo into active compounds of the present invention (NatureReviews of Drug Discovery, 2008, 7:255). It is noted that in manyinstances, the prodrugs themselves also fall within the scope of therange of compounds according to the present invention. The prodrugs ofthe compounds of the present invention can be prepared by standardorganic reaction, for example, by reacting with a carbamoylating agent(e.g., 1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, orthe like) or an acylating agent. Further examples of methods andstrategies of making prodrugs are described in Bioorganic and MedicinalChemistry Letters, 1994, 4:1985.

Certain isotopically-labelled compounds of the various Formulae (e.g.,those labeled with ³H and ¹⁴C) are useful in compound and/or substratetissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e.,¹⁴C) isotopes are particularly preferred for their ease of preparationand detectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labelled compounds of the various Formulaecan generally be prepared by following procedures analogous to thosedisclosed in the Schemes and/or in the Examples herein below, bysubstituting an appropriate isotopically labelled reagent for anon-isotopically labelled reagent.

Deuterium-enriched compounds: deuterium (D or 2H) is a stable,non-radioactive isotope of hydrogen and has an atomic weight of 2.0144.Hydrogen naturally occurs as a mixture of the isotopes xH (hydrogen orprotium), D (2H or deuterium), and T (3H or tritium). The naturalabundance of deuterium is 0.015%. One of ordinary skill in the artrecognizes that in all chemical compounds with a H atom, the H atomactually represents a mixture of H and D, with about 0.015% being D.Thus, compounds with a level of deuterium that has been enriched to begreater than its natural abundance of 0.015%, should be consideredunnatural and, as a result, novel over their nonenriched counterparts.

The present disclosure is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. In particular one,some, or all hydrogens may be deuterium. Radioactive isotopes may beused, for instance for structural analysis or to facilitate tracing thefate of the compounds or their metabolic products after administration.By way of general example and without limitation, isotopes of hydrogeninclude deuterium and tritium and isotopes of carbon include C-13 andC-14.

It should be recognized that the compounds of the present invention maybe present and optionally administered in the form of salts, andsolvates. For example, it is within the scope of the present inventionto convert the compounds of the present invention into and use them inthe form of their pharmaceutically acceptable salts derived from variousorganic and inorganic acids and bases in accordance with procedures wellknown in the art.

When the compounds of the present invention possess a free base form,the compounds can be prepared as a pharmaceutically acceptable acidaddition salt by reacting the free base form of the compound with apharmaceutically acceptable inorganic or organic acid, e.g.,hydrohalides such as hydrochloride, hydrobromide, hydroiodide; othermineral acids such as sulfate, nitrate, phosphate, etc.; and alkyl andmonoarylsulfonates such as ethanesulfonate, toluenesulfonate andbenzenesulfonate; and other organic acids and their corresponding saltssuch as acetate, tartrate, maleate, succinate, citrate, benzoate,salicylate and ascorbate. Further acid addition salts of the presentinvention include, but are not limited to: adipate, alginate, arginate,aspartate, bisulfate, bisulfite, bromide, butyrate, camphorate,camphorsulfonate, caprylate, chloride, chlorobenzoate,cyclopentanepropionate, digluconate, dihydrogenphosphate,dinitrobenzoate, dodecylsulfate, fumarate, galacterate (from mucicacid), galacturonate, glucoheptaoate, gluconate, glutamate,glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate,hippurate, 2-hydroxyethanesulfonate, iodide, isethionate, iso-butyrate,lactate, lactobionate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, oxalate, oleate, pamoate, pectinate,persulfate, phenylacetate, 3-phenylpropionate, phosphonate andphthalate. It should be recognized that the free base forms willtypically differ from their respective salt forms somewhat in physicalproperties such as solubility in polar solvents, but otherwise the saltsare equivalent to their respective free base forms for the purposes ofthe present invention.

When the compounds of the present invention possess a free acid form, apharmaceutically acceptable base addition salt can be prepared byreacting the free acid form of the compound with a pharmaceuticallyacceptable inorganic or organic base. Examples of such bases are alkalimetal hydroxides including potassium, sodium and lithium hydroxides;alkaline earth metal hydroxides such as barium and calcium hydroxides;alkali metal alkoxides, e.g., potassium ethanolate and sodiumpropanolate; and various organic bases such as ammonium hydroxide,piperidine, diethanolamine and N-methylglutamine. Also included are thealuminum salts of the compounds of the present invention. Further basesalts of the present invention include, but are not limited to: copper,ferric, ferrous, lithium, magnesium, manganic, manganous, potassium,sodium and zinc salts. Organic base salts include, but are not limitedto, salts of primary, secondary and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, e.g., arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, iso-propylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris-(hydroxymethyl)-methylamine(tromethamine). It should be recognized that the free acid forms willtypically differ from their respective salt forms somewhat in physicalproperties such as solubility in polar solvents, but otherwise the saltsare equivalent to their respective free acid forms for the purposes ofthe present invention.

In one aspect, a pharmaceutically acceptable salt is a hydrochloridesalt, hydrobromide salt, methanesulfonate, toluenesulfonate, acetate,fumarate, sulfate, bisulfate, succinate, citrate, phosphate, maleate,nitrate, tartrate, benzoate, bicarbonate, carbonate, sodium hydroxidesalt, calcium hydroxide salt, potassium hydroxide salt, tromethaminesalt, or mixtures thereof.

Compounds of the present invention that comprise tertiarynitrogen-containing groups may be quaternized with such agents as (Ci-4)alkyl halides, e.g., methyl, ethyl, iso-propyl and tert-butyl chlorides,bromides and iodides; di-(C1_4) alkyl sulfates, e.g., dimethyl, diethyland diamyl sulfates; alkyl halides, e.g., decyl, dodecyl, lauryl,myristyl and stearyl chlorides, bromides and iodides; and aryl (Ci-4)alkyl halides, e.g., benzyl chloride and phenethyl bromide. Such saltspermit the preparation of both water- and oil-soluble compounds of theinvention.

Amine oxides, also known as amine-N-oxide and N-oxide, of anti-canceragents with tertiary nitrogen atoms have been developed as prodrugs(Mal. Cancer Therapy, 2004 March; 3(3):233-244). Compounds of thepresent invention that comprise tertiary nitrogen atoms may be oxidizedby such agents as hydrogen peroxide (H₂O₂), Caro's acid or peracids likemeta-Chloroperoxybenzoic acid (mCPBA) to from amine oxide.

Pharmaceutical Compositions

The invention encompasses pharmaceutical compositions comprising thecompound of the present invention and pharmaceutical excipients, as wellas other conventional pharmaceutically inactive agents. Any inertexcipient that is commonly used as a carrier or diluent may be used incompositions of the present invention, such as sugars, polyalcohols,soluble polymers, salts and lipids. Sugars and polyalcohols which may beemployed include, without limitation, lactose, sucrose, mannitol, andsorbitol. Illustrative of the soluble polymers which may be employed arepolyoxyethylene, poloxamers, polyvinylpyrrolidone, and dextran. Usefulsalts include, without limitation, sodium chloride, magnesium chloride,and calcium chloride. Lipids which may be employed include, withoutlimitation, fatty acids, glycerol fatty acid esters, glycolipids, andphospholipids.

In addition, the pharmaceutical compositions may further comprisebinders (e.g., acacia, cornstarch, gelatin, carbomer, ethyl cellulose,guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose,povidone), disintegrating agents (e.g., cornstarch, potato starch,alginic acid, silicon dioxide, croscarmellose sodium, crospovidone, guargum, sodium starch glycolate, Primogel), buffers (e.g., tris-HCL,acetate, phosphate) of various pH and ionic strength, additives such asalbumin or gelatin to prevent absorption to surfaces, detergents (e.g.,Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors,surfactants (e.g., sodium lauryl sulfate), permeation enhancers,solubilizing agents (e.g., glycerol, polyethylene glycerol,cyclodextrins), a glidant (e.g., colloidal silicon dioxide),anti-oxidants (e.g., ascorbic acid, sodium metabisulfite, butylatedhydroxyanisole), stabilizers (e.g., hydroxypropyl cellulose,hydroxypropylmethyl cellulose), viscosity increasing agents (e.g.,carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum),sweeteners (e.g., sucrose, aspartame, citric acid), flavoring agents(e.g., peppermint, methyl salicylate, or orange flavoring),preservatives (e.g., Thimerosal, benzyl alcohol, parabens), lubricants(e.g., stearic acid, magnesium stearate, polyethylene glycol, sodiumlauryl sulfate), flow-aids (e.g., colloidal silicon dioxide),plasticizers (e.g., diethyl phthalate, triethyl citrate), emulsifiers(e.g., carbomer, hydroxypropyl cellulose, sodium lauryl sulfate, methylcellulose, hydroxyethyl cellulose, carboxymethylcellulose sodium),polymer coatings (e.g., poloxamers or poloxamines), coating and filmforming agents (e.g., ethyl cellulose, acrylates, polymethacrylates)and/or adjuvants.

In one embodiment, the pharmaceutical compositions are prepared withcarriers that will protect the compound against rapid elimination fromthe body, such as a controlled release formulation, including implantsand microencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions(including liposomes targeted to infected cells with monoclonalantibodies to viral antigens) can also be used as pharmaceuticallyacceptable carriers. These can be prepared according to methods known tothose skilled in the art, for example, as described in U.S. Pat. No.4,522,811.

Additionally, the invention encompasses pharmaceutical compositionscomprising any solid or liquid physical form of the compound of theinvention. For example, the compounds can be in a crystalline form, inamorphous form, and have any particle size. The particles may bemicronized, or may be agglomerated, particulate granules, powders, oils,oily suspensions or any other form of solid or liquid physical form.

When compounds according to the present invention exhibit insufficientsolubility, methods for solubilizing the compounds may be used. Suchmethods are known to those of skill in this art, and include, but arenot limited to, pH adjustment and salt formation, using co-solvents,such as ethanol, propylene glycol, polyethylene glycol (PEG) 300, PEG400, DMA (10-30%), DMSO (10-20%), NMP (10-20%), using surfactants, suchas polysorbate 80, polysorbate 20 (1-10%), cremophor EL, Cremophor RH40,Cremophor RH60 (5-10%), Pluronic F68/Poloxamer 188 (20-50%), SolutolHS15 (20-50%), Vitamin E TPGS, and d-a-tocopheryl PEG 1000 succinate(20-50%), and using advanced approaches such as micelle, addition of apolymer, nanoparticle suspensions, and liposome formation.

A wide variety of administration methods may be used in conjunction withthe compounds of the present invention. Compounds of the presentinvention may be administered or coadministered topically, orally,intraperitoneally, intravenously, intraarterially, transdermally,sublingually, intramuscularly, rectally, transbuccally, intranasally,liposomally, via inhalation, vaginally, intraoccularly, via localdelivery (for example by catheter or stent), subcutaneously,intraadiposally, intraarticularly, intrathecally, transmucosally,pulmonary, or parenterally, for example, by injection, includingsubcutaneous, intradermal, intramuscular, intravenous, intraarterial,intracardiac, intrathecal, intraspinal, intracapsular, subcapsular,intraorbital, intraperitoneal, intratracheal, subcuticular,intraarticular, subarachnoid, and intrasternal; by implant of a depot orreservoir, for example, subcutaneously or intramuscularly. For example,the administering may be combined with myostatin inhibitors,anti-inflammatory agents, and gene therapy to reduce pathogenic DUX4protein production in FSHD by controlling D4Z4 methylation, suppressingDUX4 mRNA, and inhibiting DUX4 pathways. For example, the administeringmay be combined with small interfering RNA (siRNA), small hairpin RNA(shRNA), microRNA (miRNA), CRISPR gene editing, and antisenseoligonucleotides directed at DUX4 and downstream transcripts.

The compounds according to the invention may also be administered orcoadministered in slow release dosage forms. Compounds may be ingaseous, liquid, semi-liquid or solid form, formulated in a mannersuitable for the route of administration to be used. For oraladministration, suitable solid oral formulations include tablets,capsules, pills, granules, pellets, sachets and effervescent, powders,and the like. Suitable liquid oral formulations include solutions,suspensions, dispersions, syrups, emulsions, oils and the like. Forparenteral administration, reconstitution of a lyophilized powder istypically used.

Suitable doses of the compounds for use in treating the diseases ordisorders described herein can be determined by those skilled in therelevant art. Therapeutic doses are generally identified through a doseranging study in humans based on preliminary evidence derived from theanimal studies. Doses must be sufficient to result in a desiredtherapeutic benefit without causing unwanted side effects. Mode ofadministration, dosage forms and suitable pharmaceutical excipients canalso be well used and adjusted by those skilled in the art. All changesand modifications are envisioned within the scope of the present patentapplication.

In some embodiments, a compound described herein may be administered ata dosage from about 1 mg/kg to about 60 mg/kg, or more. For example, thecompound may be administered to a subject at a dosage of 5, 10, 15, 20,25, 40, 35, 40, 45, 50, 55, or 60 mg/kg, or within a range between anyof the proceeding values, for example, between about 30 mg/kg and about40 mg/kg, between about 5 mg/kg and about 20 mg/kg, and the like. Inanother embodiment, a compound described herein may be administered at adosage from about 1 mg/kg to about 20 mg/kg. For example, the compoundmay be administered to a subject at a dosage of 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg/kg, or within a rangebetween any of the proceeding values, for example, between about 10mg/kg and about 15 mg/kg, between about 6 mg/kg and about 12 mg/kg, andthe like. In another embodiment, a compound described herein isadministered at a dosage of ≤15 mg/kg. For example, a compound may beadministered at 15 mg/kg per day for 7 days for a total of 105 mg/kg perweek. For example, a compound may be administered at 10 mg/kg twice perday for 7 days for a total of 140 mg/kg per week.

In many embodiments, the dosages described herein may refer to a singledosage, a daily dosage, or a weekly dosage.

In one embodiment, a compound may be administered up to 120 mg/kg perday.

In one embodiment, a compound may be administered up to 840 mg/kg perweek

In one embodiment, a compound may be administered once per day. Inanother embodiment, a compound may be administered twice per day. Insome embodiments, a compound may be administered three times per day. Insome embodiments, a compound may be four times per day.

In some embodiments, a compound described herein may be administered 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, or 24 times per week. In other embodiments, the compound isadministered once biweekly.

In some embodiments, a compound described herein may be administeredorally.

In some embodiments, a compound described herein may be administeredorally at a dosage of ≤15 mg/kg once per day.

In some embodiments, the compound of Formula (V′) may be administeredorally at a dosage of ≤15 mg/kg once per day.

In some embodiments, a compound described herein is administered orallyat ≤15 mg/kg twice per day.

In some embodiments, the compound of Formula (V′) may be administeredorally at a dosage of ≤15 mg/kg twice per day.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The dosage regimen utilizing the disclosed compound is selected inaccordance with a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal orhepatic function of the patient; and the particular disclosed compoundemployed. A physician or veterinarian of ordinary skill in the art canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the condition.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated.

-   -   ASO antisense oligonucleotides    -   DAPI 4′,6-diamidino-2-phenylindole (dihydrochloride)    -   DMSO dimethyl sulfoxide    -   DUX4 double homeobox 4    -   DUX4-fl double homeobox 4 full length    -   FSHD facioscapulohumeral muscular dystrophy    -   gRNA guide RNA    -   MBD3L2 methyl CpG binding domain protein 3 like 2    -   MHC myosin heavy chain    -   MPAK14 mitogen-activated protein kinase 14    -   mRNA messenger RNA    -   MYOG myogenin (myogenic factor 4)    -   p HSP27 phosphorylated heat shock protein 27    -   PCR polymerase chain reaction    -   pLAM polyadenylation signal sequence    -   POLR2A RNA Polymerase II Subunit A    -   qPCR quantitative polymerase chain reaction    -   RNA ribonucleic acid    -   sgRNA single guide RNA    -   siRNA small interfering RNA

EXAMPLES

The disclosure is further illustrated by the following examples, whichare not to be construed as limiting this disclosure in scope or spiritto the specific procedures herein described. It is to be understood thatthe examples are provided to illustrate certain embodiments and that nolimitation to the scope of the disclosure is intended thereby. It is tobe further understood that resort may be had to various otherembodiments, modifications, and equivalents thereof which may suggestthemselves to those skilled in the art without departing from the spiritof the present disclosure.

Materials and Methods Materials: Human Skeletal Muscle Myoblasts:

FTCE-00016-01 (immortalized FSDH myoblast line, 6.3 repeats) andisogenic lines A4 control healthy normal and C12 FSHD myoblasts wereused for all studies (as described in Mamchaoui et al., 2011; Thorley etal., 2016). Four distinct patient myoblast lines, FTCE-016, -020, -197,-196 were provided by R. Tawil. The FSHD myoblasts were shown to expressaberrant DUX4 via demethylation of the D4Z4 on chromosome 4q35.

Media Components and Tissue Culture Materials Included:

Skeletal Muscle Growth Medium (PromoCell, C-23160) supplemented with 15%FBS (Hyclone, SH30071) and Pen/Strep (Gibco, 15140148). Skeletal MuscleCell Differentiation Medium (PromoCell, C-23061) supplemented with 20%KnockOut Serum Replacement (Gibco, 10828010) and Pen/Strep(Differentiation media). EmbryoMax 0.1% Gelatin Solution (EMDmilliporeES-006-B). PBS (Gibco, 10010023), Tissue culture treated 96-wellmicroplate (Corning, CLS3595), TC-Treated Multiwell Cell Culture Plat(Falcon, 353046).

Real Time PCR Reagents and Kits:

Lysis buffer-Roche Realtime Ready lysis buffer 19.5 μL. (for 20 μL)(Roche, 07248431001), DNAse I (Ambion, AM2222) 0.25 μL, Protector RNaseInhibitor (Roche, 3335402001) 0.25 μL. RNeasy Micro Kit (Qiagen, 74004),Taqman Preamp Master Mix (ThermoFisher Scientific, 4391128), TaqmanMultiplex Master Mix (ThermoFisher Scientific, 4484262), ZSCAN4 TaqmanAssay (ThermoFisher Scientific, Hs00537549 ml, FAM-MGB), MYOG TaqmanAssay (ThermoFisher Scientific, Hs01072232_ml, JUN-QSY), RPLP0 TaqmanAssay (ThermoFisher Scientific, Hs99999902_ml), LEUTX Taqman Assay(ThermoFisher Scientific, Hs00418470_ml).

Antisense Oligonucleotides (ASOs)

ASOs were purchased from Exiqon: FTSE-000001 (DUX4 ASO from Exiqon,CAGCGTCGGAAGGTGG (SEQ ID NO: 1), 300610)), Non-targeting ASO (Exiqon,AACACGTCTATACGC (SEQ ID NO: 2), 300610)

Gelatin Coating of Tissue Culture Dishes:

Performed three days prior to treatment, 0.1% gelatin solution was madeby combining 1 g gelatin (e.g. Sigma G9391) and 1 L tissue culture gradewater; autoclave for 30 minutes to dissolve and sterilize. Sufficient0.1% gelatin to coat the using a sterile pipette, aspirate the solutionuntil all of the dishes have been coated. Air dried and store inoriginal sleeve at room temperature.

Cell Plating: Performed three days prior to treatment, 10000 cells wereplated per well on gelatinized 96-well plates, or 100000 cells ongelatinized 6-well plates.

Antisense Oligonucleotide and Compound Treatment:

For ASO or compound treatments cells were plate into 100 μL of Promocellgrowth medium containing ASO or compounds at the describedconcentrations.

Skeletal Muscle Myotube Differentiation:

On day 0, change to differentiation media. Remove plates from theincubator and aspirate the growth medium, Wash once with PBS, 100 μL for96-wells and 1 mL for a 6-well plate, Add 100 μL or 2 mL ofdifferentiation medium per well, 96- or 6-well respectively. Addantisense oligonucleotides or drug at the desire concentration and putback in the incubator. Fusion should start within day 1-2. Incubate for3-4 days.

RNA Preparation:

Cells were removed from the incubator and media aspirated. Quickly lysedfollowing one of the following protocols: For lysis in 96-well platesdirect lysis and one-step RT-Preamp qPCR protocol described below. Foreach 96-well prepare a mix containing: 19.5 μL Roche Realtime Readylysis buffer, 0.25 μL RNAse inhibitor, 0.25 μL DNAseI (from Thermo notthe included one in the kit). 20 μL of the mix was added to each well,mix 5 times and incubated 5 minutes at RT or alternatively shakenvigorously for 15 minutes. Lysis was observed under the microscope.Samples were frozen −80° C. at least for 15 minutes,

qPCR One Step:

For qPCR, dilute 1:10 and use 2 μL for a 10 μL 1-step RT-qPCR reaction.For detection of GAPDH, RPLP0, TBP, MYOG, FRG1, MYH3, ACTN2, etc.). Per10 μL reaction: RNA (1:10 dilution lysate) 2 μL, Fast Advanced TaqmanMaster Mix (2×) 5 μL, RT enzyme mix (40×) 0.25 μL, Taqman probe set(20×) 0.5 μL, H₂0 2.25 μL. The following reaction protocol was run onthe QuantStudio 7: 48° C. for 15 min, 50° C. for 2 min, 95° C. for 30sec, 40×, 95° C. for 5 sec, 60° C. for 30 sec, then plates were read asspecified by the manufacturer (Thermo). For 1-step RT-Preamplificationused for detection of DUX4 downstream genes, i.e. MBD3L2, ZSCAN4, LEUTX,TRIM43, KHDC1L. POL2RA-VIC was used as Endogenous control). Per 10 μLreaction: RNA (1:10 dilution lysate) 2.25 μL, Taqman Pre-Amp Master Mix(2×) 5 μL, RT enzyme mix (40×) 0.25 μL, Taqman probe set (0.2×)*2.5μL, * Pooling the TaqMan Assays: equal volumes of each 20× TaqMan® GeneExpression Assay, up to 100 assays were combined. For example, to pool50 TaqMan assays, 10 μL of each assay were combined in a microcentrifugetube. The pooled TaqMan assays were diluted using 1× TE buffer so thateach assay is at a final concentration of 0.2×. For the above example,add 500 μL of 1× TE buffer to the pooled TaqMan assays for a total finalvolume of 1 mL. The QuantStudio7 protocol was used 48° C. 15 min, 95° C.10 min, 10 cycles: 95° C. 15 sec, 60° C. 4 min, 4° C. infinite. Sampleswere then diluted to 50 μL and continue with the qPCR step. Per 10 μLreaction: Preamp dilution 2 μL, Fast Advanced Taqman Master Mix (2×) 5μL, Taqman probe set (20×) 0.5 μL, H₂0 2.5 μL. When multiplexing thevolume was adjusted to 10 μL total). The following program was run onthe QuantStudio7: 50° C. for 2 min, 95° C. for 30 sec, 40×, 95° C. for 5sec, 60° C. for 30 sec, plates were read as per the manufacturersspecifications (Thermo).

Methods for Total RNA Extraction from Myotubes Using RNeasy Micro PlusKit:

In a 6 well plate, 450 μL Buffer RLT Plus was added. Lysate washomogenized by transfer the lysate to a gDNA Eliminator spin columnplaced in a 2 mL collection tube (supplied), centrifuged for 30 s at≥8000×g (≥10,000 rpm) and discarded column while saving theflow-through. Then 250 μL of Ethanol (35% final) was added to theflow-through, and mixed well by pipetting, not centrifuged. Then sampleswere transferred, including any precipitate that may have formed, to anRNeasy MinElute spin column placed in a 2 mL collection tube (supplied).Then centrifuged for 15 s at ≥8000×g. Flow-through was discarded orcollected for Protein precipitation. 700 μL Buffer RW1 to the RNeasyMinElute spin column was added then centrifuge for 15 s at ≥8000×g. anddiscard the flow-through. DNAse treatment was performed by gently mixing10 pL DNAseI with 70 μL of Buffer RDD and added directly to the column,incubated at room temperature for 20 min. Then, 700 μL Buffer RW1 (permanufactures specification) to the RNeasy MinElute spin column,centrifuged for 15 s at ≥8000×g. and the flow-through discarded. 500 μLBuffer RPE was added to the RNeasy MinElute spin column centrifuged for15 s at ≥8000×g and discarded the flow-through. 500 μL of 80% ethanolwas added to the RNeasy MinElute spin column, centrifuged for 2 min at≥8000×g to wash the spin column membrane and the collection tube wasdiscarded with the flow-through. The RNeasy MinElute spin column wasplaced in a new 2 mL collection tube (supplied) centrifuged at fullspeed for 5 min to dry the membrane and the collection tube wasdiscarded with the flow through. RNeasy MinElute spin column was placedin a new 1.5 mL collection tube (supplied). 14 μL RNase-free water wasadded directly to the center of the spin column membrane, andcentrifuged for 1 min at full speed to elute the RNA. You should end upwith about 12 μL of eluted RNA.

Detection of DUX4-Fl Using Method Described by Himeda et al. 2015:

cDNA preparation. Per 10 μL reaction: RNA (1 μg) 1 μL, Oligo dT 0.5 μL,10 mM dNTPs 0.5 μL, H₂0 4.5 μL, Samples were Incubated at 65° C. for 2min and quickly move to ice and held at least 1 min before adding theenzyme mix, 5× First strand Buffer 2 μL, 0.1M DTT 0.5 μL, RNAseinhibitor 0.5 μL, SSIV RT 0.5 μL, samples were incubated at 55° C. for20 min and 80° C. for 10 min, with cool down to 4° C. DUX4pre-amplification was performed: Per 10 μL reaction, RT reaction 1 μL,5× GC buffer 2 μL, DMSO 0.8 μL, 10 mM dNTPs 0.2 μL, 10 μM TJ38F 0.2 μL,10 μM TJ40R 0.2 μL, Phusion II DNA pol 0.1 μL, H₂0 5.5 μL. The followingprotocol was run on the QuantStudio 7: 98° C. 2 min, 10 cycles of 98°C., 15 seconds, 64° C., 20 seconds, 72° C., 15 seconds, 4° C. infinite.DUX4 qPCR with nested primers: per 10 μL reaction, DUX4 preamplification DNA 1 μL, 2× IQ SYBR Mix 5 μL, 10 μM TJ38F 0.4 μL, 10 μMTJ41R 0.4 μL, H₂0 3.2 μL. The following protocol was run on theQuantStudio7 95° C. 3 min, 40 cycles of, 95° C. 10 seconds, 64° C. 15seconds, 72° C. 20 seconds, 86° C. 10 seconds then read plate onQuantStudio7 as per manufactures instruction (Thermo). Ct values wereextracted from the QuantStudio Realtime PCR software and Genedata wasused to calculate relative levels of expression using POLR2A as ahousekeeping gene.

FSHD Myotube Immunocytochemistry

Briefly, cells were fixed in 4% paraformaldehyde and permeabilized in 4%paraformaldehyde (PFA) for 10 min at room temperature. Cells werepermeabilized with PBST (1×PBS solution with 0.1% Triton X-100) beforeblocking with 10% Normal Donkey Serum or 3% BSA (NDS) in PBST. Cellswere then incubated with appropriately diluted primary antibodies inPBST with 5% NDS for 1 hours at room temperature or 12 hours at 4° C.,washed with PBST for 3 times at room temperature and then incubated withdesired secondary antibodies in TBST with 5% NDS and DAPI to counterstain the nuclei. DUX4 was detected by immunocytochemistry using theE5-5 antibody in differentiated FSHD myotubes. Activated Caspase-3 wasdetected cell signaling antibody that we're using for ICC, Asp175(https://www.cellsignal.com/products/primary-antibodies/cleaved-caspase-3-asp175-antibody/9661).

RNAseq Methods

The 40 bp single-end reads from Illumina had good quality by checkingwith FastQC (http://www.bioinformatics.babraham.ac.uk/projects/fastqc/).Reads were mapped to hg19 using TopHat v2.1.1. The gene model for TopHatwas created by merging known Gene in gtf format with kgXref table. Bothknown Gene and kgXref were downloaded from UCSC table browser in hg19assembly. The read counts were obtained using feature Counts functionfrom Subread package with strandness option as -r 2. Reads werenormalized with DESeq2. The biological replicates in the neuron samples,processed at different time periods, have batch effect as suggested byprinciple component analysis. Consequently, Combat was used for reducingthis batch effect. Calculated standard RPKM expression values. Totalgene signature is very small and defined at standard statisticalcutoffs: 86/19,799 mRNA genes. DUX4-regulated gene signature is majorityof total signature: 77/86 mRNA genes=90%. Non-DUX4 regulated genes isminority of total signature with moderate fold changes: 9/86 mRNAgenes=10%; 2-2.7× log FC.

Methods for siRNA and Cas9/sgRNA RNP Transduction of FSHD Myotubes:

Synthetic crRNAs were purchased from Thermo Fisher Scientific andannealing to tracrRNAs was performed according to specifications. Inshort, crRNAs and tracrRNA were resuspended in TE buffer at 100 μM,mixed, and diluted 5-fold in annealing buffer. Annealing was performedin a ProFlex PCR system following manufacturers recommendation. 100 ngof assembled crRNA:tracrRNA were incubated with 500 ng of TrueCut Cas9(ThermoFisher, #A36497) in the resuspension buffer provided with theNeon transfection system kit (ThermoFisher, #MPK10096). After 15 minuteincubation the reaction was used to transfect 50.000 myoblasts accordingto the methods described. Sequences used for the targeting of MAPK14 (3sgRNAs) and pLAM region (polyadenylation sequence of DUX4, 4 gRNAs)were:

NT-CTRL, (SEQ ID NO: 3) GTATTACTGATATTGGTGGG; MAPK14, (SEQ ID NO: 4)GCTGAACAAGACAATCTGGG, (SEQ ID NO: 5) CTGCTTTTGACACAAAAACG,(SEQ ID NO: 6) CTTATCTACCAAATTCTCCG; pLAM, (SEQ ID NO: 7)AGAATTTCACGGAAGAACAA, (SEQ ID NO: 12) CAGGTTTGCCTAGACAGCGT,(SEQ ID NO: 8) ATTAAAATGCCCCCTCCCTG, (SEQ ID NO: 9)AATCTTCTATAGGATCCACA. siRNA MAPK14, Antisense: (SEQ ID NO: 10)UAGAUUACUAGGUUUUAGGTC, (SEQ ID NO: 11) CCUAAAACCUAGUAAUCUATT

EXPERIMENTAL Example 1 Repression of DUX4 Using Sequence DirectedAntisense Oligonucleotide Reduces Downstream Target Genes

Wild type myotubes were treated with DMSO control vehicle, and maturepatient-derived FSHD myotubes that express DUX4 protein were treatedwith DMSO vehicle control or 1 μM of a DUX4 sequence-directed antisenseoligonucleotide (ASO; FTX-2) purchased from Exiqon. After treatment, themyotubes were lysed in 19.5 μL of Roche Real Time Ready Lysis Buffer,0.25 μL of DNAse1 (Ambion, AM2222), 0.25 μL of Protector RNase Inhibitor(Roche, 3335402001), and the RNA was collected in an RNeasy Micro KitMaster Mix. Expression levels of DUX4-regulated downstream genes(ZSCAN4, TRIM43, MBD3L2, LEUTX, and KHDC1L) was determined by real timePCR (ThermoFisher Scientific, 4484262), ZSCAN4 Taqman Assay(ThermoFisher Scientific, Hs00537549_ml, FAM-MGB), MYOG Taqman Assay(ThermoFisher Scientific, Hs01072232_ml, JUN-QSY), RPLP0 Taqman Assay(ThermoFisher Scientific, Hs99999902_ml), and/or LEUTX Taqman Assay(ThermoFisher Scientific, Hs00418470_ml). Ct values were extracted fromQuantStudio Realtime PCR software, and Genedata was used to calculaterelative levels of expression using POLR2A as a housekeeping gene.

The results showed that FSHD myotubes treated with DUX4 sequencedirected ASO express reduced amounts of DUX4 and the DUX4 downstreamtranscription factor target genes, ZSCAN4, TRIM43, MBD3L2, LEUTX, andKHDC1L, as compared to FSHD myotubes treated with DMSO vehicle control(FIG. 2).

The data in FIG. 3A are grouped plate quality control data comparingexpression of MBD3L2 mRNA in FSHD myotubes treated with DMSO control or1 μM DUX4 ASO, and healthy normal isogenic control myotubes. FIG. 3Bshows pharmacologic quality control data and dose dependent reduction ofDUX4 and the downstream gene, MBD3L2, using different dilutions of theDUX4 ASO. FIG. 3C shows plate based assay statistics comparing FSHDmyotubes treated with DMSO to WT: Z′ is 0.512 and Signal to Noise (S/N)is 5.1, and FSHD myotubs treated with DMSO or DUX4 ASO:Z′ is 0.319 andSignal to Noise (S/N) is 4.6.

Example 2 P38 Small Molecule Inhibitors Reduce MBD3L2 mRNA Expression

Wild type myotubes and mature patient-derived FSHD myotubes that expressDUX4 protein were treated with DMSO vehicle control or multipleconcentrations of various p38α/β inhibitors with different ranges ofisoform and kinome selectivity, including SB239063 (FIG. 4A; IC₅₀=15nM), VX-702 (FIG. 4B), Pamapimod (FIG. 4C), and TAK-715 (FIG. 4D). Aftertreatment, the control and treated cells were processed for realtime PCRquantification of MBD3L2 mRNA (DUX4 downstream gene) and myogenin (MYOG)mRNA (control) expression. These p38α/β inhibitors showed potent (IC50approximately <10 nM, FIGS. 4A-D) reduction of MBD3L2 mRNA expressionwith no impact to MYOG mRNA expression in FSHD myotubes.

In FSHD myotubes, p38 kinase inhibitors (e.g., Pamapimod)dose-dependently reduced DUX4 mRNA and DUX4 downstream gene MBD3L2 mRNAexpression without impacting myotube formation. When compared to DMSOtreatment, 10, 100, and 1000 nM FTX000839 (Pamapimod) dose-dependentlyreduced both DUX4-fl and MBD3L2 downstream gene mRNA levels normalizedto POLR2A mRNA, as measured by qPCR and Taqman in FSHD myotubes (FIG.5A) without impacting differentiation into myotubes (FIG. 5B). The datashow that p38 kinase inhibitors dose-dependently reduce MBD3L2 mRNAexpression without impacting myogenin mRNA expression.

Example 3 P38 MAPK14 mRNA and MBD3L2 mRNA Reduction Via siRNA Knockdown

p38α MAPK14 85 and p38α MAPK14 86 siRNAs were transfected into patientFSHD myotubes as described in Materials and Methods. Each of p38α MAPK1485 siRNA and p38α MAPK14 86 siRNA (to a lesser extent) reduced p38MAPK14 expression, as shown in FIG. 6A, and MBD3L2 mRNA (DUX4 targetgene) expression, as shown in FIG. 6B, as compared to non-target controlsiRNAs (NT CTRL 1 and NT CTRL 2). The data shows that genomic reductionof p38α MAPK14 >50% specifically reduced DUX4 and downstream targetgenes, as exemplified by MBD3L2.

Example 4 MBD3L2 mRNA Reduction Via P38α Kinase Cas9/sgRNA RNPs

CRISPR gRNA targeting of MAPK14 or pLAM (polyadenylation signal sequencefor DUX4) was conducted as described in Materials and Methods. CRISPRgRNA targeted to MAPK14 or pLAM (polyadenylation signal sequence forDUX4) resulted in a reduction in expression of MBD3L2 but no MYOG. Thedata indicates that genomic reduction of p38α MAPK14 specificallyreduced DUX4 and downstream target genes, as exemplified by MBD3L2.

Example 5 FTX-1821 Downregulates DUX4 Protein and MBD3L2 mRNA

Patient-derived FSHD myotubes (with 6 repeats of D4Z4 arrays) weretreated with DMSO vehicle control and different FTX-1821 concentrations,and DUX4 protein and MBD3L2 mRNA levels were determined as described inMethods and Materials. For DUX4 and MBD3L2, four biological replicateswere analyzed. In addition, pHSP27 levels were determined. For pHSP27quantification, three replicates were obtained in two independentexperiments.

Treatment of the FSHD patient derived myotubes with FTX 1821 resulted ina concentration-dependent reduction of DUX4 protein (IC₅₀=25 nM) andMBD3L2 mRNA (IC₅₀=25 nM) that correlated with the changes observed inphospho HSP27 levels (IC₅₀=10 nM) as evidence of target engagement (FIG.7). The results were indicative of a concentration-dependent reductionof DUX4 protein (IC₅₀=25 nM) and MBD3L2 mRNA (IC₅₀=10 nM). Thereductions in DUX4 protein and MBD3L2 mRNA correlated with the observedchanges in p-HSP27 levels (IC₅₀=10 nM) as evidence of target engagement.These results indicate that p38α pathway inhibition by FTX-1821 resultsin potent DUX4 protein and MBD3L2 mRNA downregulation.

Example 6 FTX-1821 does not Affect Myotube Formation

Immortalized FHSD myotubes were differentiated and treated with DMSOvehicle control or FTX-1821 at concentrations of 1 μM, 0.33 μM, 0.11 μM,or 0.037 μM. After 4 days, the cells were fixed and stained withantibodies directed against MHC or DAPI. See FIG. 8A. The nuclei inmyotubes were quantified according to MHC staining (FIG. 8B). Theresults showed no changes in myotube formation or fusion after treatmentwith FTX-1821 at concentrations tested.

Example 7 FTX-1821 Reduces Apoptosis in FSHD Myotubes

Apoptosis was measured by active Caspase-3 levels in FSHD myotubes invitro as described in Materials and Methods. Apoptosis was detected in asporadic manner in a subset of myotubes in culture as shown by the whitecircles and magnified region in FIG. 9A. Active Caspase-3 signal wasquantified in FSHD myotubes that had been treated with FTX-1821 atdifferent concentrations (FIG. 9B). The results showed a dose-dependentreduction of apoptotic signal, as indicated by the reduction indetection of active Caspase 3 (IC₅₀=45 nM), and this effect was specificto FSHD myotubes compared to control myotubes. No change in activeCaspase-3 signal was observed following DMSO treatment.

Example 8 FTX-1821 Reduces Pathologic DUX4 Transcriptional ProgramExpression

Studies were conducted as described in Methods and Materials to identifygenes in the DUX4 pathway whose expression in down-regulated by in FSHDmyotubes treated with FTX-1821 as compared to FSHD myotubes treated withDMSO vehicle control. In addition, gene expression was also determinedin wild type myotubes treated with DMSO. Three replicates for eachcondition were analyzed by RNA-seq and genes were clustered by thedirection and intensity of change.

As shown in the heatmap of FIG. 10A, a number of differentiallyexpressed genes were identified by RNA-seq profiling. The bar indicatesthe normalized changes observed, e.g., genes that were downregulated byFTX-1821 are enriched in samples treated with only DMSO. The expressionof these genes was normalized upon treatment with FTX-1821 (1 μM) andcloser resembled the observations in wild type cells. Calculated usingstandard RPKM expression values, the total gene signature was very smalland defined at standard statistical cutoffs: 86/19,799 mRNA genes.DUX4-regulated gene signature was a majority of the total signature, andthese genes are listed in FIG. 10A. Non-DUX4-regulated genes wereminority of the total signature with moderate fold changes: 9/86 mRNAgenes=10%; 2-2.7× log FC. FIG. 10B shows the normalized reads, asdescribed in Materials and Methods, of the DUX4 target genes that weredownregulated upon treatment with FTX-1821. Three independent replicatesper group were analyzed.

Example 9 Reduction of MBD3L2 mRNA in Various FSHD1 Genotypes andPhenotypes

The ability of p38 kinase inhibitors to reduce expression of DUX4 targetgenes in cells obtained from patients having various different FSHD1genotypes was conducted as described in Methods and Materials. Fourdistinct FSHD patient myoblast lines, i.e., FTCE-016, -020, -197, and-196 (kindly provided Rabi Tawil) were treated with FTX-1821 (1 μM) orFTX-839 (1 μM), and mRNA levels of the DUX4 target gene, MBD3L2, weredetermined following treatment.

MBD3L2 expression levels were reduced in all of the FSHD lines,resulting in levels similar to those measured in healthy controls,FTCE-396 and FTCE-014 (FIG. 11). This is evidence of DUX4 target genereduction by p38 kinase inhibitors across myotubes derived from diverseFSHD1 genotypes and phenotypes (similar results were observed for FSHD2,data not shown).

Example 10 Reduction of MBD3L2 mRNA from FSHD1 and FSHD2 Genotypes andPhenotypes

To assess the treatment effect of p38 selective inhibition usingFTX-1821 in FSHD1 and FSHD2 cells, primary myoblast lines were kindlyprovided by Rabi Tawil at the University of Rochester. FIG. 13summarizes the genotypes and phenotypes of 13 FSHD1 and 3 FSHD2 patientmyoblasts used in the study. The various FSHD1 and FSHD2 myoblasts weretreated with DMSO, FTX-1821 or FTX-839 (1 μM), and following treatment,mRNA expression levels of the DUX4 target gene, MBD3L2, were determined.In addition, apoptosis was determined by measuring active caspase-3 inthe FSHD1 and FSHD2 lines.

Each of the various FSHD1 and FSHD2 myoblasts showed a reduction ofMBD3L2 (FIG. 14A, top 11 lines). The reduction resulted in expressionlevels similar to those in healthy control lines (CTRL-FTCE-014) (FIG.14A, bottom 2 lines). In addition, treatment with FTX-839 showed areduction in apoptosis across both FSHD1 and FSHD2 lines, to a levelthat was similar to the amount determined in a healthy control line(CTRL-FTCE-014) (FIG. 14B). These results indicate that clinical FSHDbiopsy myoblasts, when differentiated into myotubes, show a reduction inboth pathologic DUX4 downstream gene expression and resulting cell deathacross both FSHD1 and FSHD2 genotypes and phenotypes.

Example 11 Target Engagement in Muscle of Wild Type Rats FollowingTreatment with a Potent and Selective P38 Kinase Inhibitor

The pharmacokinetic properties of FTX-1821 were studied in an animalmodel. FTX-1821 was orally dosed to fasted or unfasted maleSprague-Dawley rats (N=6 animals per time point and treatment group),and phospho p38α: total p38α levels were determined. Pharmacodynamicanalysis of p38 system target engagement in muscle tissue was performedby measuring the change in phosphor MAP kinase-activated protein kinase2 (MK2) to total MK2 ratio before and after drug treatment. All methodsused are described in the Materials and Methods section.

FTX-1821 exhibited plasma pharmacokinetic properties similar to thosedescribed previously (Aston et al., 2009; data not shown). These studiesadditionally demonstrated rapid distribution of FTX-1821 to multiplemuscles and plasma. Muscle to plasma exposure ratios were equal to orgreater than 1 in the rat when clinically relevant plasma exposures wereachieved.

Pharmacodynamic analysis demonstrated that a single, oral dose ofFTX-1821 (0.3 mg/kg) resulted in clinically relevant plasmaconcentrations (Barbour et al., 2012) and significantly decreased thephospho MK2 to total MK2 ratio in rat trapezius muscle within 1-hour ofdrug treatment (FIG. 15). P38 system target engagement persisted for atleast 12 hours following the single dose of FTX-1821 (FIG. 15). P38system target engagement in trapezius muscel was maximal when plasma andmuscle concentrations of FTX-1821 were greater than 20 ng/mL or ng/g anddeclined at timepoints when exposures decreased. The muscleconcentrations of FTX-1821 achieved in the rat study are predicted toresult in >70% reduction at Cmax in DUX4 dependent target genes in FSHDpatient muscle biopsies based upon in vitro data in FSHD myotubes(above).

This pharmacokinetic and pharmacodynamic analysis indicated that maximalinhibition of the p38 system in muscle was achieved when plasma FTX-1821concentrations were greater than 20 ng/mL and that significant p38pathway inhibition would be expected, in human muscle, with clinicaldoses of 7.5 or 15 mg BID (Barbour et al., 2012).

Example 12 Inhibition of the DUX4 Genomic Program in FSHD XenograftedMice Following Treatment with a Potent and Selective P38 KinaseInhibitor

FSHD and control muscle xenograft mice were generated by xenografting C6(FSHD) and A4 (control) IPSC-derived human immortalized isogenicmyoblast cell lines into the bilateral tibialis anterior (TA) muscles ofapproximately 8-week old male Nod-Rag mice as described by Sakellariouet al., 2016. Following the 4-week long engraftment and INMES procedure,the FSHD xenografted animals were treated with BID injections of eithervehicle or FTX-2865 (10 mg/kg) for 8 days (a total of 14 injections) andwere sacrificed at approximately the time of maximal plasmaconcentrations (Tmax) 1-hour after the final morning injection on Day 8.At sacrifice, plasma, trapezius muscle and bilateral tibialis anteriormuscles were collected and flash frozen for analysis of pharmacokineticendpoints, target engagement and DUX4 dependent mRNAs. MBD3L2 wasassessed by qPCR using a human specific probe and was normalized to thehousekeeping gene CDKN1B. pMK2 and MK2 protein concentrations wereassessed by a quantitative MSD assay.

Analysis of TA tissue by qPCR from animals engrafted for 4-6 weeks withA4 or C6 myoblast tissues demonstrated a significant (p<0.05)and >10-fold increase in MBD3L2 and other Dux4 dependent genes (notshown) in the FSHD (C6) vs control (A4) xenografted TA muscles (FIG.16). N=8 TA samples per group.

Treatment of FSHD xenografted animals with the potent and selective p38kinase inhibitor, FTX-2865, produced p38 system target engagement, asmeasured by a change in phospho MAP kinase-activated protein kinase 2(MK2) to total MK2 ratio of >50% in the TA and trapezius muscles ofwild-type mice following repeated BID administration of a 10 mg/kg dosegiven via intraperitoneal (IP) injection (data not shown). FTX-2865treatment significantly (p<0.05) decreased the ratio of phospho to totalMK2 in mouse trapezius muscle, indicating significant p38 systemengagement and also indicating sufficient drug concentrations in theskeletal muscles of the animals to inhibit the p38 system by >80% (FIG.17; N=8 trapezius samples per group). In addition, FTX-286 treatmentsignificantly (p<0.05) decreased the expression of MBD3L2 in the FSHDxenografted TA muscles compared to vehicle treated animals, indicatingsuppression of the pathologic DUX4 gene program by p38 inhibition (FIG.18; N=5-7 TA samples per group).

EQUIVALENTS

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand other variations thereof will be apparent to those of ordinary skillin the art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

Furthermore, it is intended any method described herein may be rewritteninto Swiss-type format for the use of any p38 kinase inhibitor or agentdescribed herein, for the manufacture of a medicament, in treating anyof the disorders described herein. Likewise, it is intended for anymethod described herein to be rewritten as a compound for use claim.

For example, use of a p38 kinase inhibitor, for the manufacture of amedicament, for treating a disorder responsive to p38 kinase inhibition,wherein the p38 kinase inhibitor is characterized by Formula (V′):

or a stereoisomer thereof, an isotopically-enriched compound thereof, aprodrug thereof, a solvate thereof, or a pharmaceutically acceptablesalt thereof; wherein the disorder is associated with DUX4 geneexpression, and the p38 kinase inhibitor reduces DUX4 expression levelsand/or the expression of one or more downstream genes in cells of thesubject.

What is claimed is:
 1. A method for treating facioscapulohumeralmuscular dystrophy (FSHD), the method comprising administering to asubject in need thereof, an effective amount of a p38 kinase inhibitor,wherein the p38 kinase inhibitor is characterized by Formula (V′):

or a pharmaceutically acceptable salt thereof; wherein administration ofthe p38 kinase inhibitor reduces expression levels of a DUX4 polypeptideand/or a polypeptide encoded by a DUX4 downstream gene in muscle cellsof the subject.
 2. The method of claim 1, wherein the DUX4 downstreamgene is selected from the group consisting of: ZSCAN4, LEUTX, PRAMEF2,TRIM43, MBD3L2, KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49,PRAMEF4, PRAME6, PRAMEF15, and ZNF280A.
 3. The method of claim 1,wherein the muscle cells are terminally differentiated muscle cells. 4.The method of claim 1, wherein the muscle cells comprise a dysregulatedD4Z4 array at chromosome 4q35.
 5. The method of claim 1, wherein thefacioscapulohumeral muscular dystrophy is FSHD type 1 (FSHD1).
 6. Themethod of claim 5, wherein the muscle cells comprise a deletion of oneor more macrosatellite D4Z4 repeats in the subtelomeric region ofchromosome 4q35.
 7. The method of claim 6, wherein the muscle cellcomprises less than 11 macrosatellite D4Z4 repeats in the subtelomericregion of chromosome 4q35.
 8. The method of claim 1, wherein thefacioscapulohumeral muscular dystrophy is FSHD type 2 (FSHD2).
 9. Themethod of claim 8, wherein the muscle cells comprise one or moremutations in a Structural Maintenance Of Chromosomes Flexible HingeDomain Containing 1 (SMCHD1) gene.
 10. The method of claim 1, whereinthe muscle cells comprise at least one non-deleted 4qA allele.
 11. Themethod of claim 1, wherein the administering causes a decrease in muscledegeneration in the subject.
 12. The method of claim 1, wherein theadministering causes a reduction in apoptosis of muscle cells in thesubject.
 13. The method of claim 1, wherein the compound of Formula V′or the pharmaceutically acceptable salt thereof is administered at adose of 7.5 mg or 15 mg.
 14. The method of claim 1, wherein the compoundof Formula V′ or the pharmaceutically acceptable salt thereof isadministered at a dose of 7.5 mg.
 15. The method of claim 13, whereinthe compound of Formula V′ or the pharmaceutically acceptable saltthereof is administered at a dose of 15 mg.
 16. The method of claim 13,wherein the compound of Formula V′ or the pharmaceutically acceptablesalt thereof is administered two times per day.
 17. The method of claim1, wherein the compound of Formula V′ or the pharmaceutically acceptablesalt thereof is administered to the subject parenterally.
 18. The methodof claim 1, wherein the compound of Formula V′ or the pharmaceuticallyacceptable salt thereof is administered to the subject orally.
 19. Themethod of claim 1, further comprising administering another p38 kinaseinhibitor agent to the subject.